SEARCH

SEARCH BY CITATION

Keywords:

  • aging;
  • Hutchinson–Gilford progeria syndrome;
  • lamin A;
  • lamin B1;
  • LMNA ;
  • nuclear lamina;
  • progerin;
  • transcription

Summary

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson–Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.


Hutchinson–Gilford progeria syndrome

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

Humans express four major lamin proteins: lamin B1 (LB1), lamin B2 (LB2), and lamins A and C (LA, LC), encoded by LMNB1, LMNB2, and LMNA genes, respectively. Lamins A, LB1, and LB2 are expressed as prelamins that contain a carboxyl-terminal CaaX motif. The cysteine in the CaaX motif undergoes farnesylation, followed by cleavage of the last three amino acids (aaX) and methyl esterification. While LB1 and LB2 remain farnesylated, LA undergoes additional cleavage of the last 15 amino acids and becomes nonfarnesylated.

The most frequent mutation in Hutchinson–Gilford progeria syndrome (HGPS), affecting approximately 90% of patients, is a de novo autosomal dominant, single base substitution mutation in LMNA (C1824T). This mutation activates a cryptic splice site, which produces a mutant LA protein with an internal deletion of 50 amino acids that disrupts the last cleavage step of prelamin A. This truncated LA, termed progerin, is permanently farnesylated, toxic to cells and displays altered structural and biochemical properties (De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003). While LA is present both at the nuclear periphery and at nuclear interior, progerin localizes predominantly at the nuclear periphery (Capell et al., 2005; Glynn & Glover, 2005). Progerin expression leads to reduction in the protein levels of lamin B1, thus further disrupting the nuclear lamina (Capell et al., 2005; Scaffidi & Misteli, 2005; Taimen et al., 2009; Shimi et al., 2011)

In HGPS patients, progerin affects mostly tissues of mesenchymal origin, including bone, skin, fat, teeth, hair, and blood vessels, while mortality is primarily due to accelerated atherosclerosis. The most prominent HGPS cellular phenotypes are nuclear lobulation, heterochromatin alterations, mitochondrial dysfunction, and chromosomal and telomeres aberrations. Altered nuclear functions include compromised cell-cycle regulation, impaired DNA repair, increased apoptosis and senescence (Merideth et al., 2008; Burtner & Kennedy, 2010; Mehta et al., 2011; Trigueros-Motos et al., 2011; Fig. 1) The molecular mechanisms by which progerin causes tissue-specific effects, and the reasons for the similarities or differences between HGPS phenotypes and those of aging are largely obscure. Noteworthy, the cryptic splice site activated in HGPS to create progerin is also used at low frequency in healthy individuals. Increased progerin levels are found in cells with physiological aging (Scaffidi & Misteli, 2006; McClintock et al., 2007; Olive et al., 2010). Furthermore, reduced lamin B1 protein expression is also observed in human cells undergoing senescence where the loss of LB1 probably leads to activation of either p53 or pRb pathways and has been proposed to serve as a senescence-associated biomarker (Shimi et al., 2011; Freund et al., 2012).

image

Figure 1. Nuclear phenotypes in Hutchinson–Gilford progeria syndrome (HGPS) cells. (A) HGPS cells show aberrant nuclei with reduced expression of lamin B. The panel is taken with permission from Scaffidi & Misteli (2005). (B) Changes in nuclear structure and progressive nuclear pore complexes alterations occur at later passage number. (a) and (b) are cells from passage 6, (c) and (d )are cells from passage 24. The panel is taken with permission from Goldman et al. (2004). (C) Transmission electron microscope analysis shows nuclear envelope changes in HGPS cells. (a) Nuclear envelope invaginations. (b) Nuclear lamina thickening and peripheral heterochromatin loss. (c) Control nuclei with normal lamina and heterochromatin organization. The panel is taken with permission from Goldman et al. (2004). (D) HGPS cells show reduced H3K9me3. The data were taken with permission from Columbaro et al. (2005). (E) HGPS cells show chromosomal break (a), sister chromatid fusion (b) and free chromosomal end due to short undetected telomere (c). The panel is taken with permission from Benson et al. (2010). (F) HGPS cells have compromised DNA repair. (a) BJ: control cells. BJ + CPT: γ-H2AX colocalization with Rad51 in Camptothecin-treated cells. HGPS: impaired γ-H2AX colocalization with Rad51 in HGPS cells. (b) HGPS: γ-H2AX colocalization with XPA in HGPS cells. The panel was taken with permission from Liu et al. (2008). (G) Altered transcript distribution in HGPS cells. Nonuniform distribution of BrU labeling in HGPS cells compared with controls. The data were taken with permission from Columbaro et al. (2005).

Download figure to PowerPoint

General mechanisms of lamin-regulated gene expression

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

Gene expression is dependent on chromatin–nuclear lamina interactions, miRNA regulation, sequestration of specific transcription factors (TFs), and interactions with RNA polymerase II (pol II) transcription machinery (Gruenbaum et al., 2003; Malhas & Vaux, 2009; Fiserova & Goldberg, 2010; Mattout et al., 2011; Zwerger et al., 2011; Jung et al., 2012).

Although there are few examples for lamin-dependent gene activation (e.g., NF-ĸB and TonEBP/NFAT5 transcription pathways), generally lamins and lamin-associated proteins provide a repressive chromatin environment due to specific protein–chromatin interactions (Lammerding et al., 2004; Favale et al., 2007; Peric-Hupkes & van Steensel, 2010; Puckelwartz et al., 2011). The specific lamin-based complexes control binding to and release of lamin-associated proteins from the nuclear periphery, including emerin, MAN1, LAP2, LBR, SUN-1, and others (Wilson & Foisner, 2010). These lamin-based complexes probably regulate gene silencing and activation of developmentally regulated genes. (Nili et al., 2001; Somech et al., 2005; Holaska & Wilson, 2006; Meister et al., 2010; Bank & Gruenbaum, 2011; Mattout et al., 2011).

The nuclear lamina association with specific gene regulatory sequences requires the transcriptional repressor cKrox in a complex with histone deacetylase 3 and Lap2β, as well as methylation of histone 3 on lysine 9 (H3K9) (Towbin et al., 2012; Zullo et al., 2012). Mutations in lamins perturb lamin–chromatin interactions, spatial arrangement of chromosome territories and intranuclear chromosome folding (Scaffidi & Misteli, 2005; Mewborn et al., 2010; Mattout et al., 2011; Mehta et al., 2011; Puckelwartz et al., 2011; van Steensel, 2011).

Lamins provide a protein scaffold for the organization of TFs. The disruption of the nuclear lamina, especially that of LB1, affects DNA replication and leads to a significant reduction in pol II activity (Moir et al., 2000; Spann et al. 2002; Ljungman & Lane 2004; Shumaker et al. 2008: Musich & Zou, 2011). Lamins A interacts with several components of pol II transcription machinery, including nuclear actin, nuclear myosin 1, chromatin remodeling complexes, and ribonucleoproteins (Sasseville & Langelier, 1998; Bengtsson & Wilson, 2004; Columbaro et al., 2005; Simon et al., 2010; Euskirchen et al., 2011). The reduction in LB1 levels, the reduction of intracellular TATA-binding protein levels, and the diminished global transcription in progerin-expressing fibroblasts all provide important insights into the role of lamins in transcriptional regulation (Candelario et al., 2011).

Lamin A and actin

Actin polymers and nuclear myosin play a key role in transcription regulation by affecting chromatin remodeling and movement, as well as by forming complexes that facilitate progress of the transcription machinery along the DNA template (Visa & Percipalle, 2010). In vitro binding between lamin and actin, and actin polymerization assays mapped two actin-binding sites in the LA tail domain (Simon et al., 2010; Simon & Wilson, 2011). The in vitro study showed significant reduction in LA-actin binding and consequently, in LA-induced actin bundling in various diseases resulting from mutations in the C-tail domain of LA, including the HGPS deletion. Hence, it is possible that lamins, and in particular LA, regulate transcription by directly affecting actin polymerization.

Lamin and progerin interactions with miRNA

miRNAs are small RNA molecules that are involved in post-transcriptional regulation by binding to target mRNAs, usually resulting in translational repression and gene silencing. LMNA and LMNB1 expression is regulated by specific miRNAs. For example, miR-23 down-regulates LMNB1 (Lin & Fu, 2009) and the brain-specific miR-9 down-regulates LA and progerin, but not lamin C and might thus bear relevance to the absence of primary central nervous system involvement in HGPS (Jung et al., 2012). Lamins can regulate the expression of specific miRNAs. For example, LB1 binds and sequesters Oct1 (Malhas & Vaux, 2009). Insufficient LB1 yields unsequestered active Oct1, which leads to excess production of mir-31. In turn, mir-31 binds and silences p16(Ink4a)/p14(Arf) mRNA which normally inhibit progress through the cell cycle by maintaining the pRb checkpoint (p16/Ink4a) and augmenting p53 levels and function (p14/Arf) (Malhas et al., 2010). LB1 reduction in HGPS cells and over-activation of mir-31 might thus explain, at least in part, the initial phase of hyperproliferation that characterizes HGPF fibroblasts prior to their apoptotic death (Bridger & Kill, 2004).

Lamins, HGPS, and mechanotransduction

Mechanotransduction describes a mechanism by which cells adjust to changes in the mechanical load exerted by their environment in part by activating specific gene expression programs. The mechanotransduction properties of cells require lamins and emerin function and are probably mediated through LINC complexes that link the nuclear lamina with the actin cytoskeleton and the NF-kB transcription pathway (Starr, 2007; Zwerger et al., 2011). Lamin A-deficient cells have decreased nuclear stiffness and increased nuclear fragility (Broers et al., 2004; Lammerding et al., 2004). In response to mechanical stress, these cells display defective mechanotransduction and attenuated NFkB response, with impaired induction of mechano-sensitive and anti-apoptotic genes (Lammerding et al., 2004, 2005; Lammerding & Lee, 2005). Hutchinson-Gilford progeria syndrome fibroblasts, which are characterized by stiffer and less compliant nuclei, are also more sensitive to mechanical strain and react with cell apoptosis/necrosis and impaired strain-induced proliferation response (Lammerding et al., 2004; Dahl et al., 2006; Verstraeten et al., 2008).

In the vascular tree, HGPS cells fail to cope with fluid shear stress and thus contributing to vascular smooth muscle cells (VSMCs) loss and atherosclerosis (Verstraeten et al., 2008; Olive et al., 2010). The increased stiffness of HGPS fibroblasts suggests an increase in mechanical sensitivity and aberrant mechanotransduction of the progerin-expressing cells, including cells of the arterial walls. Notably, evaluation of NFkB in HGPS cells has not been reported yet. Deposition of progerin in the arterial walls might render HGPS cells more sensitive to mechanical strain and contribute to the aberrant mechanotransduction (Olive et al., 2010; Zwerger et al., 2011)

Lamin-regulated transcription mechanisms are altered in HGPS

The normal transcription pattern, particularly of genes encoding TFs, is altered in HGPS cells as indicated by genome-wide expression studies. (Csoka et al., 2004; Scaffidi & Misteli, 2008; Hernandez et al., 2010; Marji et al., 2010; Plasilova et al., 2011). In the next section, we discuss specific mechanisms by which lamins regulate and progerin deregulates gene expression in HGPS cells.

Chromatin organization and modifications

Several studies support LA involvement in higher order chromatin organization and anchorage, heterochromatin formation, histone modifications, and transcriptional activity (Dechat et al., 2010; Gonzalez-Suarez & Gonzalo, 2010). The critical role of LA in chromatin organization is evident by the properties of progerin-containing HGPS nuclei that show loss of peripheral heterochromatin and specific changes in chromatin-modifying enzymes such as decreased H3 Lys 27 methyltransferase (EZH2), decrease in the chromatin modifications H3K27m3, H3K9m3, and increased in H4K20m3 (Scaffidi & Misteli, 2006; Shumaker et al., 2006; Shimi et al., 2011). These epigenetic changes affect chromatin organization, transcription, senescence, and DNA repair. Interestingly, the specific profile of HGPS-associated histone modifications oppose those which have been found in several tumors and may thus explain in part the divergent HGPS phenotypes of premature aging and cancer rarity (Dimauro & David, 2009; Chi et al., 2010).

Telomeric heterochromatin

Telomere integrity is essential for maintaining chromosomes integrity and is therefore a key determinant of aging, cancer, and the viability of stem cells (Blasco, 2005). Telomere dysfunction results in genomic instability, activation of DNA damage responses (DDR), mitochondrial dysfunction, and stem cell exhaustion, which have all been implicated in the aging process (Sahin & Depinho, 2010). Interestingly, recent studies suggest possible interconnections between these aging effectors, thus linking DNA damage and metabolic pathways through a proposed ‘telomere - p53 – mitochondrial’ axis. Dysfunctional telomeres, recognized as DNA damage, activate p53, promote senescence, and compromises mitochondrial function due to PGC1 repression. Mitochondrial dysfunction, in turn, further aggravates functional decline of tissue stem cells and telomere dysfunction, thus setting up a vicious circle. The essential role of short telomeres in premature aging and the suggested telomere–mitochondrion link are demonstrated by Werner syndrome, which encompasses premature aging and a concomitant metabolic disorder of insulin-resistant diabetes (Sahin & Depinho 2012).

Loss of LA expression as well as increased expression of progerin cause gross telomere abnormalities, including telomere attrition and mislocalization. This phenotype is normally observed in cells undergoing senescence including HGPS fibroblasts (Raz et al., 2008; Gonzalez-Suarez et al., 2009; Benson et al., 2010). Intriguingly, a recent report pointed to a synergistic relationship between progerin production and telomere dysfunction during the induction of cellular senescence in normal human fibroblasts; The progressive telomere damage during cellular senescence plays a causative role in activating progerin production, while expression of progerin causes telomere shortening (Cao et al., 2011). This finding lends insight into the process of normal aging in which progerin levels are increased (Scaffidi & Misteli, 2006; McClintock et al., 2007; Olive et al., 2010). The progerin-induced telomere dysfunction activates DDR and p53-signaling pathways leading to senescence (Benson et al., 2010). In HGPS, the induction of senescence by DDR and p53 might substantially reduce stem cell populations and contribute to premature aging (Gotzmann & Foisner, 2006; Halaschek-Wiener & Brooks-Wilson, 2007). Activation of p53 in HGPS also augments mitochondrial dysfunction and stem cells exhaustion in part by repressing the mitochondrial PGC1 protein (Halaschek-Wiener & Brooks-Wilson, 2007; Sahin & Depinho, 2010; Sahin et al., 2011). Given that telomere attrition and dysfunction and mitochondrial dysfunction are both associated with cardiovascular disease (CVD) and atherosclerosis, they might also be implicated in HGPS-related atherosclerotic CVD (Calado & Young, 2009; Puddu et al., 2009; Viteri et al., 2010). Moreover, in the presence of activated p53, short telomeres suppress tumorigenesis, despite genomic instability, thus potentially contributing to cancer rarity in HGPS (Blasco, 2005).

Chromatin remodeling

Lamins A interacts with the nucleosome remodeling and deacetylation (NuRD) complex through association with RBBP4/7. Site of interaction is localized at the LA region (amino acids 562–664) that overlaps the region deleted in progerin. This interaction is crucial to form and maintain heterochromatin foci, H3K9 methylation and heterochromatin protein 1 gamma (HP1γ) chromatin association (Meshorer & Gruenbaum, 2009; Pegoraro et al., 2009). Indeed, silencing of individual NuRD subunits in normal cells recapitulated aging-associated chromatin defects, including heterochromatin loss. The inability of progerin to bind RBBP4/7 is likely responsible for the reduction in several NuRD proteins and the loss of peripheral heterochromatin in HGPS cells (Meshorer & Gruenbaum, 2009; Pegoraro et al., 2009).

LINC complexes in HGPS

Besides the impaired role of the LINC complexes in mechanotransduction, LA binding to the nuclear membrane SUN1 protein plays a key role in the etiology of HGPS (Crisp et al., 2006; Haque et al., 2006, 2010). Hutchinson-Gilford progeria syndrome cells display increased SUN1 levels at the nuclear envelope as SUN1 preferentially interacts with prelamin A/progerin (Goldman et al., 2004; Haque et al., 2010; Chen et al., 2012). Down-regulation of SUN1 by RNAi in HGPS cells restores nuclear shape, prevents the heterochromatin loss, and inhibits senescence (Chen et al., 2012).

Barrier-to-autointegration factor in HGPS

The distinct effects of LA on peripheral heterochromatin organization are further exemplified by LA interactions with the barrier-to-autointegration factor (BAF). Barrier-to-autointegration factor is involved in tethering heterochromatin to the nuclear envelope via its interactions with DNA, histones, RBBP4, LA, and LEM-domain proteins (Shumaker et al., 2001; Montes de Oca et al., 2009). Notably, the 50-amino acids deletion that characterizes progerin does not interfere with progerin-BAF binding. Binding of BAF to progerin as well as to LA and prelamin A result in loss of BAF cytoplasmic pool, and in its partial dysfunction probably due to loss of BAF interactions with the chromatin-organizing protein RBBP4 (Capanni et al., 2010). Interestingly, a recessive mutation in BAF causes segmental premature-aging syndrome that resembles HGPS but lacks atherosclerosis (Puente et al., 2011).

Altered regulation of specific transcription factors in HGPS

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

The interactions between lamins and various TFs–regulate tissue-specific transcriptional programs and lead in most cases to transcriptional repression (Mattout-Drubezki & Gruenbaum, 2003). The interactions operate through specific protein–protein interactions, via sequestration of TFs to the nuclear periphery and by affecting nuclear pore complexes (NPCs) positioning and function (Heessen & Fornerod, 2007; Andrés & González, 2009; Marmiroli et al., 2009; Fiserova & Goldberg, 2010). A summary of TFs that are regulated directly or indirectly by lamin A/progerin and their relevance to HGPS pathology is shown in Table 1. PRX1 (Kubben et al., 2010), MEOX/GAX (Csoka et al., 2004), and TWIST2 (Plasilova et al., 2011) appear only in Table 1. Moreover, progerin expression disrupts the Ran gradient and reduces the function of the SUMOylation pathway (Kelley et al., 2011). These effects might contribute to the compromised nucleo-cytoplasmic transport of TFs through the NPC. Furthermore, SUMO pathway disruption might also compromise the regulation of lamin A by SUMO2 (Zhang & Sarge, 2008), SUMO3 (Galisson et al., 2011), and SUMO1 (Simon et al., 2013). Interestingly, Farnesyl transferase inhibitor (FTIs) treatment has been found to prevent progerin effects on the Ran-GTPase system, a fact that might further expand FTIs therapeutic yield (Kelley et al., 2011).

Table 1. Possible effects of lamins/progerin-related transcription factors on HGPS phenotypes
TFsKnown status in HGPSResultant cellular characteristicsProposed related clinical characteristics
  1. CVD, cardiovascular disease; ECM, extra cellular matrix; HC, heterochromatin; HGPS, Hutchinson–Gilford progeria syndrome; ING1, inhibitor-of-growth-protein1; VSMCs, vascular smooth muscle cells.

pRbDysfunction

Genomic instability: mitotic defects, chromosomal mis-segregation

HC disorganization

histone modifications

Premature aging
Increased apoptosis (via E2F1,E2F3)Cancer rarity
Impaired osteogenesisBone abnormalities
Impaired adipogenesisLipodystrophy
Increased fibrosisFibrosis: skin, blood vessels
ING1

Aberrant cytoplasmic sequestration

Reduced nuclear levels

HC disorganization and loss of peripheral HC

Compromised DNA repair

Premature aging
SREBP1

Altered localization

Impaired PPARγ signaling

Impaired adipogenesis

Lipodystrophy

CVD – PPARγ related

NotchAltered pathway activationStem cell exhaustionPremature aging
Mesenchymal stem cells dys: impaired adipogenesis impaired osteogenesisLipodystrophy bone abnormalities
VSMCs pathologyVasculopathy, CVD atherosclerosis
NFκβAltered response to mechanical strain (in LA-deficient cells)

Increased mechanosensitivity

Increased apoptosis /necrosis

Premature aging

atherosclerosis

VSMCs pathologyVasculopathy, CVD, atherosclerosis
Wnt-β-catenin

Down-regulated

Altered LEF1 localization & activity

Stem cells exhaustionPremature aging

Mesenchymal stem cells dys:

impaired adipogenesis

impaired osteogenesis

Lipodystrophy bone abnormalities
Defective ECM

Premature aging

Skin abnormalities

Abnormal dentition

Vasculopathy

Decreased tumorigenesisCancer rarity
Prx1

Preferential progerin binding

Down-regulated interaction with Tenascin-C

Defective ECMSee above: in Wnt
Altered skeletogenesisBone abnormalities
VSMCs pathologyVasculopathy, CVD, atherosclerosis
MEOX2/GAXUp-regulatedVSMCs pathologyVasculopathy, CVD, atherosclerosis
TWIST 2Down-regulatedImpaired osteogenesisBone abnormalities

pRb

The retinoblastoma tumor suppressor (pRb) protein regulates numerous TFs and determines cell-fate and differentiation (Burkhart & Sage, 2008). Lamins A and its associated protein LAP2α interact with the pRb, as well as with inhibitor-of-growth-protein1 (ING1). These interactions probably regulate pRb association with HP1, histones, and chromatin remodeling enzymes and contribute to chromatin recruitment to the nuclear periphery (Gonzalo & Blasco, 2005). Genome-wide expression studies identified the LA-pRb-signaling network as a major pathway affected in HGPS (Marji et al., 2010). Indeed, loss of LA activity leads to mislocalization, increased proteasomal degradation and inactivation of pRb (Johnson et al., 2004; Nitta et al., 2007; Andrés & González, 2009; Boban et al., 2010).

TGFβ

Binding of LA and LAP2α to pRb probably modulates TGFβ effects on fibroblasts proliferation. Moreover, LA inhibits TGFβ-induced fibroblast proliferation by its effects on PP2A, which promotes pRb and Smads 2/3 dephosphorylation (Van Berlo et al., 2005). Lamins A also associates with MAN1 (Mansharamani & Wilson, 2005), which also regulates Smads phosphorylation and sequestration (Lin et al., 2005; Pan et al., 2005; Van Berlo et al., 2005; Ishimura et al., 2006; Cohen et al., 2007). Disruption of these interactions might lead to uncontrolled fibroblasts proliferation and fibrosis, thus contributing to HGPS-related sclerotic skin abnormalities and atherosclerotic CVD (Blobe et al., 2000; Merideth et al., 2008). Notably, the prominent adventitial fibrosis is a major characteristic of the ‘atypical’ HGPS atherosclerotic CVD along with primary loss of medial VSMCs, deposition of progerin and changes in the composition of the extracellular matrix (Merideth et al., 2008; Olive et al., 2010).

Runx2

pRb also affects osteogenesis and bone development by binding and potentiating Runx2, which is involved in the development and maintenance of bone and cartilage (Thomas et al., 2001). Lamins A silencing impairs osteoblastogenesis indicating that it is critical for bone development (Akter et al., 2009; Rauner et al., 2009). Nevertheless, direct LA–Runx2 interaction has not been documented

SREBP

Aberrant interaction of progerin with TFs can also account for impaired adipogenesis normally controlled by the SREBP1- and PPARγ transcriptional pathways (Capanni et al., 2005; Siersbaek et al., 2010; Duband-Goulet et al., 2011). Nevertheless, SREBP1 binds with high affinity to prelamin A, as well as to progerin resulting in SREBP1 sequestration at the nuclear envelope with concomitant reduction in its intranuclear availability and thus in reduced transcriptional activity of its target genes. In addition, PPARγ is down-regulated and adipocyte differentiation is inhibited in cultured pre-adipocytes (Capanni et al., 2005; Maraldi et al., 2008). As PPARγ also has anti-inflammatory and anti-atherosclerotic activities (Takano & Komuro, 2009), its suppression might enhance CVD in HGPS patients.

Inhibitor-of-growth-protein1

The inhibitor-of-growth-protein1 (ING1) is a member of the ING family of proteins. The ING proteins play a key role in cell-cycle progression, apoptosis, cell aging, and DDR. Inhibitor-of-growth-protein1 functions in the nucleus as an epigenetic regulator by binding to epigenetic determinants mostly on histone H3 and to either histone acetylase or deacetylase complexes (Soliman & Riabowol, 2007). Inhibitor-of-growth-protein1 binds to the N-terminal region of LA rod domain (amino acids 1–406) (Han et al., 2008). The inability of progerin to bind ING1 at physiological levels suggests that the tail region of lamins profoundly affects the ability of the rod domain to interact with ING1. Lamins A association stabilizes ING1 and targets it to the nucleus (Han et al., 2008). In cells, where ING1-LA association is abrogated, ING1 protein levels are markedly reduced, and it is aberrantly sequestered in the cytoplasm. Re-expression of LA in LA-null cells restored ING1 expression and nuclear localization (Han et al., 2008). A model has been proposed according to which tethering by LA has a dual function: it stabilizes ING1 as well as spatially regulates its epigenetic activity (Soliman & Riabowol, 2007; Han et al., 2008). The reduced ING1-LA association in HGPS cells can help to explain the loss of peripheral chromatin in these cells. Nevertheless, the precise role of LA-ING1 association in cellular senescence, heterochromatin formation, and its linkage to different HGPS phenotypes remains largely unknown.

Altered regulation of adult stem cells in HGPS

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

Recent studies suggest that aberrant regulation of adult stem cell likely affects premature aging in HGPS. Lamins A associates with the Notch co-activator SKIP, regulates SKIP availability and Notch transcriptional activity (Scaffidi & Misteli, 2008). Progerin has a reduced affinity to SKIP leading to an increase in its intranuclear availability and activation of downstream effectors of Notch, which in turn alter the differentiation pathways of mesenchymal stem cells. Indeed, Notch pathway components are markedly overexpressed in several mesenchymal cell line isolated from HGPS patients, while progerin interference with the Notch signaling pathway inhibits mesenchymal stem cell differentiation (Scaffidi & Misteli, 2008). The aberrant regulation of the Notch signaling pathway could account for the phenotypes of mesoderm-derived adipose, bone, and vascular smooth muscle tissues in HGPS (Rosen & MacDougald, 2006; Gridley, 2007; Canalis, 2008; Kurpinski et al., 2010; Andersson et al., 2011).

The Wnt/β-catenin pathway regulates mesenchymal stem cell proliferation and differentiation with specific roles in skeleton and cartilage development (Day et al., 2005; Chen et al., 2008). In a mouse progeria model, the extracellular matrix (ECM) of adult mice is defective and does not support fibroblasts cell proliferation. The resulting cell senescence is due to the reduced nuclear localization and transcriptional activity of the Wnt-signaling target Lef1, a phenomenon that is also observed in fibroblasts derived from HGPS patients (Hernandez et al., 2010). Microarray studies on HGPS fibroblasts and mesenchymal stem cells confirm profound misregulation of ECM genes expression (Csoka et al., 2004; Scaffidi & Misteli, 2008; Zhang et al. 2011). The gene expression alterations in HGPS fibroblasts suggest excess of ECM deposition, resulting from increased expression of ECM components and decreased expression of ECM-remodeling enzymes (Csoka et al., 2004). These findings support the hypothesis that defective ECM triggers the skeletal, dental, skin, and vascular abnormalities in HGPS (Csoka et al., 2004; Hernandez et al., 2010). Importantly, since inappropriate activation of the Wnt pathway has been related to cancer (Klaus & Birchmeier, 2008), its down-regulation in HGPS might contribute to cancer rarity despite accelerated aging.

Compromised DNA damage repair in HGPS cells

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

Hutchinson-Gilford progeria syndrome cells accumulate DNA double-strand breaks (DSBs) and show a compromised DDR attributed mainly to progerin expression, lack of functional LA, and ROS accumulation (Musich & Zou, 2011; Richards et al., 2011). The LA roles in chromatin organization and its interactions with histone H2A, emerin, ING1, and PCNA as described previously help explain its involvement in the DDR (Mattout-Drubezki & Gruenbaum, 2003; Shumaker et al., 2006; Han et al., 2008).

It has been shown that in LA-null cells, the loss of LA induces transcriptional up-regulation of the cysteine protease Cathepsin L (CTSL). This observation suggests a direct or indirect repression of CTSL by LA (Gonzalez-Suarez et al., 2011). In addition, up-regulation of CTSL was also reported in mouse model of progeria (Varela et al., 2008). By mediating transcriptional regulation of the CTSL, LA directly regulates the levels of major nonhomologous end joining and homologous recombination repair proteins such as 53BP1 and the p130/E2F4 repressor complexes, which in turn, regulate the transcription of the DNA repair proteins RAD51 and BRCA1 (Gonzalez-Suarez et al., 2011; Redwood et al., 2011). Notably, LA also stabilizes 53BP1 by preventing its proteolysis (Gonzalez-Suarez et al., 2009). Indeed, cell lines that express progerin or lack LA activity display impaired DDR pathways (Liu et al., 2005; Manju et al., 2006; Gonzalez-Suarez et al., 2011; Redwood et al., 2011). Progerin further enhances DSBs accumulation and impaired DDR by its aberrant interaction with PCNA and lack of interaction with ING1, which leads to peripheral sequestration of several replication and DNA repair factors and stalled replication forks that collapse into DSBs (Musich & Zou, 2009, 2011). In addition, the progerin-mediated loss of various NuRD subunits further compromises the DDR by perturbing NuRD roles in recruitment of DNA repair proteins, and in promoting transcriptional repression, which facilitates the repair process (Lai & Wade, 2011). In conclusion, progerin-mediated DNA damage accumulation and compromised DDR bear direct relevance to HGPS-related premature aging and deregulated transcription. Additionally, as DDR goes awry, the resultant persistent damage signaling activates p53, thus promoting senescence and tumor suppression (Collado et al., 2007).

Cancer in HGPS

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

Hutchinson–Gilford progeria syndrome is characterized by cancer rarity (Hennekam, 2006; Burtner & Kennedy, 2010). It is possible that cancer predisposition is masked by the short lifespan of the patients. Nevertheless, a unique constellation of several factors might explain the divergent HGPS phenotypes of premature aging and cancer rarity.

The potential pro-cancerous effects of DNA damage accumulation and compromised DNA repair might be counteracted by the HGPS-associated p53 activation, short telomeres, and the specific profile of histone modifications (Ljungman & Lane 2004; Campisi & d'Adda di Fagagna, 2007). Interestingly, the two cases of cancer reported thus far in HGPS patients refer to osteosarcoma (King et al., 1978; Shalev et al., 2007), which is known, in its genetic as well as its sporadic occurrence, to be related mainly to p53 or pRb dysfunction (Lerner & Antman, 2012).

Concluding remarks

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

The data reviewed hereby support the concept that the lamins-associated transcriptional regulation in HGPS cells is impaired and can explain major HGPS phenotypes (Fig. 2). Additionally, it may explain the absence of primary neuronal degeneration, the rarity of cancer, and the various differences from atherosclerotic CVD. The proposed concept integrates suitably with current molecular aging theories (Blagosklonny et al., 2010) and indicates a pivotal role for p53 in HGPS as it promotes senescence/aging, suppresses tumorigenesis and activates autophagy through its negative regulation of the mTOR pathway.

image

Figure 2. A scheme depicting the altered interactions and the related cellular effects of lamins and progerin in HGPS cells, and the projection on major HGPS phenotypes. VSMCs, vascular smooth muscle cells; ECM, extracellular matrix; actin: nuclear actin; myosin: nuclear myosin; RNPs, ribonucleoproteins. The letters in parenthesis in the box titled ‘consequences’ refer to the lettered transcription factors in the box above it, whose dysfunctions may contribute to the cellular effects.

Download figure to PowerPoint

Transcriptional deregulation in HGPS appears to be closely related to lack of normal functional LA, LB1 silencing, and disruption of lamins network integrity. It seems to play a major role in HGPS pathogenesis, adding thus to progerin insults. Moreover, in addition to current therapies, aimed to eliminate progerin and inhibit its farnesylation, there might be a place for therapeutic interventions addressing specific alterations in TFs-controlled pathways and their downstream effects. Such potential therapeutic agents include rapamycin (inhibits mTORC1 pathway), tyrosine-kinase inhibitors (block fibrosis via TGFβ signaling), statins (activate PPARγ), and ROS scavengers (decrease levels of unrepaired DSBs which interfere with transcription).

The famous saying ‘inside every old person is a young person wondering what happened’ is tragically true in HGPS in view of the speedy progression of devastating aging-phenotypes and fatal outcome. Identifying NL-associated transcriptional deregulation as a possible molecular mechanism underlying HGPS phenotypes might help understand some of the disease's mysteries, and offer an intriguing concept for future research.

Acknowledgements

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References

We thank Yuval Reiss, Eran Meshorer, Michal Goldberg and members of the Gruenbaum laboratory for their comments on the manuscript. We gratefully acknowledge funding from the Morasha Legacy 1798/10, Israel Ministry of Health (MOH 2965), the Muscular Dystrophy Association (MDA), the Israeli Science Foundation, the Binational Israel-USA Science Foundation (BSF 2007215) and the COST NANONET (BM1002).

References

  1. Top of page
  2. Summary
  3. Hutchinson–Gilford progeria syndrome
  4. General mechanisms of lamin-regulated gene expression
  5. Altered regulation of specific transcription factors in HGPS
  6. Altered regulation of adult stem cells in HGPS
  7. Compromised DNA damage repair in HGPS cells
  8. Cancer in HGPS
  9. Concluding remarks
  10. Acknowledgements
  11. References
  • Akter R, Rivas D, Geneau G, Drissi H, Duque G (2009) Effect of lamin A/C knockdown on osteoblast differentiation and function. J. Bone Miner. Res. 24, 283293.
  • Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138, 35933612.
  • Andrés V, González JM (2009) Role of A-type lamins in signaling, transcription, and chromatin organization. J. Cell Biol. 187, 945957.
  • Bank EM, Gruenbaum Y (2011) The nuclear lamina and heterochromatin: a complex relationship. Biochem. Soc. Trans. 39, 17051709.
  • Bengtsson L, Wilson KL (2004) Multiple and surprising new functions for emerin, a nuclear membrane protein. Curr. Opin. Cell Biol. 16, 7379.
  • Benson EK, Lee SW, Aaronson SA (2010) Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J. Cell Sci. 123, 26052612.
  • Blagosklonny MV, Campisi J, Sinclair DA, Bartke A, Blasco MA, Bonner WM, Bohr VA, Brosh RMJ, Brunet A, Depinho RA, Donehower LA, Finch CE, Finkel T, Gorospe M, Gudkov AV, Hall MN, Hekimi S, Helfand SL, Karlseder J, Kenyon C, Kroemer G, Longo V, Nussenzweig A, Osiewacz HD, Peeper DS, Rando TA, Rudolph KL, Sassone-Corsi P, Serrano M, Sharpless NE, Skulachev VP, Tilly JL, Tower J, Verdin E, Vijg J (2010) Impact papers on aging in 2009. Aging 2, 111121.
  • Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Genet. 6, 611622.
  • Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N. Engl. J. Med. 342, 13501358.
  • Boban M, Braun J, Foisner R (2010) Lamins: ‘structure goes cycling’. Biochem. Soc. Trans. 38, 301306.
  • Bridger JM, Kill IR (2004) Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis. Exp. Gerontol. 39, 717724.
  • Broers JL, Peeters EA, Kuijpers HJ, Endert J, Bouten CV, Oomens CW, Baaijens FP, Ramaekers FC (2004) Decreased mechanical stiffness in LMNA-/- cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies. Hum. Mol. Genet. 13, 25672580.
  • Burkhart DL, Sage J (2008) Cellular mechanisms of tumor suppression by the retinoblastoma gene. Nat. Rev. Cancer 8, 671682.
  • Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat. Rev. Mol. Cell Biol. 11, 567578.
  • Calado RT, Young NS (2009) Telomere diseases. N. Engl. J. Med. 361, 23532365.
  • Campisi J, d'Adda di, Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729740.
  • Canalis E (2008) Notch signaling in osteoblasts. Sci. Signal. 1, pe17.
  • Candelario J, Borrego S, Reddy S, Comai L (2011) Accumulation of distinct prelamin A variants in human diploid fibroblasts differentially affects cell homeostasis. Exp. Cell Res. 317, 319329.
  • Cao K, Blair CD, Faddah DA, Kieckhaefer JE, Olive M, Erdos MR, Nabel EG, Collins FS (2011) Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J. Clin. Inves. 121, 28332844.
  • Capanni C, Mattioli E, Columbaro M, Lucarelli E, Parnaik VK, Novelli G, Wehnert M, Cenni V, Maraldi NM, Squarzoni S, Lattanzi G (2005) Altered pre-lamin A processing is a common mechanism leading to lipodystrophy. Hum. Mol. Genet. 14, 14891502.
  • Capanni C, Cenni V, Haraguchi T, Squarzoni S, Schüchner S, Ogris E, Novelli G, Maraldi N, Lattanzi G (2010) Lamin A precursor induces barrier-to-autointegration factor nuclear localization. Cell Cycle 9, 26002610.
  • Capell BC, Erdos MR, Madigan JP, Fiordalisi JJ, Varga R, Conneely KN, Gordon LB, Der CJ, Cox AD, Collins FS (2005) Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 102, 1287912884.
  • Chen M, Zhu M, Awad H, Li TF, Sheu TJ, Boyce BF, Chen D, O'Keefe RJ (2008) Inhibition of beta-catenin signaling causes defects in postnatal cartilage development. J. Cell Sci. 121, 14551465.
  • Chen CY, Chi YH, Mutalif RA, Starost MF, Myers TG, Anderson SA, Stewart CL, Jeang KT (2012) Inhibition of beta-catenin signaling causes defects in postnatal cartilage development. J. Cell Sci. 121, 14551465.
  • Chi P, Allis CD, Wang GG (2010) Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457469.
  • Cohen TV, Kosti O, Stewart CL (2007) The nuclear envelope protein MAN1 regulates TGFbeta signaling and vasculogenesis in the embryonic yolk sac. Development 134, 13851395.
  • Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130, 223233.
  • Columbaro M, Capanni C, Mattioli E, Novelli G, Parnaik VK, Squarzoni S, Maraldi NM, Lattanzi G (2005) Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment. Cell. Mol. Life Sci. 62, 26692678.
  • Crisp M, Liu Q, Roux K, Rattner JB, Shanahan C, Burke B, Stahl PD, Hodzic D (2006) Coupling of the nucleus and cytoplasm: role of the LINC complex. J. Cell Biol. 172, 4153.
  • Csoka AB, English SB, Simkevich CP, Ginzinger DG, Butte AJ, Schatten GP, Rothman FG, Sedivy JM (2004) Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell 3, 235243.
  • Dahl KN, Scaffidi P, Islam MF, Yodh AG, Wilson KL, Misteli T (2006) Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 103, 1027110276.
  • Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739750.
  • De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Levy N (2003) Lamin A Truncation in Hutchinson-Gilford Progeria. Science 300, 2055.
  • Dechat T, Adam SA, Taimen P, Shimi T, Goldman RD (2010) Nuclear lamins. Cold Spring Harb. Perspect. Biol. 2, a000547.
  • Dimauro T, David G (2009) Chromatin modifications: the driving force of senescence and aging? Aging 1, 182190.
  • Duband-Goulet I, Woerner S, Gasparini S, Attanda W, Kondé E, Tellier-Lebègue C, Craescu CT, Gombault A, Roussel P, Vadrot N, Vicart P, Ostlund C, Worman HJ, Zinn-Justin S, Buendia B (2011) Subcellular localization of SREBP1 depends on its interaction with the C-terminal region of wild-type and disease related A-type lamins. Exp. Cell Res. 317, 28002813.
  • Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423, 293298.
  • Euskirchen GM, Auerbach RK, Davidov E, Gianoulis TA, Zhong G, Rozowsky J, Bhardwaj N, Gerstein MB, Snyder M (2011) Diverse roles and interactions of the SWI/SNF chromatin remodeling complex revealed using global approaches. PLoS Genet. 7, e1002008.
  • Favale NO, Sterin Speziale NB, Fernández Tome MC (2007) Hypertonic-induced lamin A/C synthesis and distribution to nucleoplasmic speckles is mediated by TonEBP/NFAT5 transcriptional activator. Biochem. Biophys. Res. Commun. 364, 443449.
  • Fiserova J, Goldberg MW (2010) Relationships at the nuclear envelope: lamins and nuclear pore complexes in animals and plants. Biochem. Soc. Trans. 38, 829831.
  • Freund A, Laberge RM, Demaria M, Campisi J (2012) Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 20662075.
  • Galisson F, Mahrouche L, Courcelles M, Bonneil E, Meloche S, Chelbi-Alix MK, Thibault P (2011) A novel proteomics approach to identify SUMOylated proteins and their modification sites in human cells. Mol. Cell. Proteomics 10, M110.004796.
  • Glynn MW, Glover TW (2005) Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum. Mol. Genet. 14, 29592969.
  • Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, Collins FS (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford Progeria Syndrome. Proc. Natl Acad. Sci. USA 101, 89638968.
  • Gonzalez-Suarez I, Gonzalo S (2010) Nurturing the genome: A-type lamins preserve genomic stability. Nucleus 1, 129135.
  • Gonzalez-Suarez I, Redwood AB, Perkins SM, Vermolen B, Lichtensztejin D, Grotsky DA, Morgado-Palacin L, Gapud EJ, Sleckman BP, Sullivan T, Sage J, Stewart CL, Mai S, Gonzalo S (2009) Novel roles for A-type lamins in telomere biology and the DNA damage response pathway. EMBO J. 28, 24142427.
  • Gonzalez-Suarez I, Redwood AB, Grotsky DA, Neumann MA, Cheng EH, Stewart CL, Dusso A, Gonzalo S (2011) A new pathway that regulates 53BP1 stability implicates cathepsin L and vitamin D in DNA repair. EMBO J. 30, 33833396.
  • Gonzalo S, Blasco MA (2005) Role of Rb family in the epigenetic definition of chromatin. Cell Cycle 4, 752755.
  • Gotzmann J, Foisner R (2006) A-type lamin complexes and regenerative potential: a step towards understanding laminopathic diseases? Histochem. Cell Biol. 125, 3341.
  • Gridley T (2007) Notch signaling in vascular development and physiology. Development 134, 27092718.
  • Gruenbaum Y, Goldman RD, Meyuhas R, Milles E, Margalit A, Fridkin A, Dayani Y, Prokocimer M, Enosh A (2003) The nuclear lamina and its functions in the nucleus. Int. Rev. Cytol. 226, 162.
  • Halaschek-Wiener J, Brooks-Wilson A (2007) Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome. J. Gerontol. A Biol. Sci. Med. Sci. 62, 38.
  • Han X, Feng X, Rattner JB, Smith H, Bose P, Suzuki K, Soliman MA, Scott MS, Burke BE, Riabowol K (2008) Tethering by lamin A stabilizes and targets the ING1 tumour suppressor. Nat. Cell Biol. 10, 13331340.
  • Haque F, Lloyd DJ, Smallwood DT, Dent CL, Shanahan CM, Fry AM, Trembath RC, Shackleton S (2006) SUN1 interacts with nuclear lamin A and cytoplasmic nesprins to provide a physical connection between the nuclear lamina and the cytoskeleton. Mol. Cell. Biol. 26, 37383851.
  • Haque F, Mazzeo D, Patel JT, Smallwood DT, Ellis JA, Shanahan CM, Shackleton S (2010) SUN1 interacts with nuclear lamin A and cytoplasmic nesprins to provide a physical connection between the nuclear lamina and the cytoskeleton. Mol. Cell. Biol. 26, 37383851.
  • Heessen S, Fornerod M (2007) The inner nuclear envelope as a transcription factor resting place. EMBO Rep. 8, 914919.
  • Hennekam RC (2006) Hutchinson-Gilford progeria syndrome: review of the phenotype. Am. J. Med. Genet. A. 140, 26032624.
  • Hernandez L, Roux KJ, Wong ES, Mounkes LC, Mutalif R, Navasankari R, Rai B, Cool S, Jeong JW, Wang H, Lee HS, Kozlov S, Grunert M, Keeble T, Jones CM, Meta MD, Young SG, Daar IO, Burke B, Perantoni AO, Stewart CL (2010) Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria. Dev. Cell 19, 413425.
  • Holaska JM, Wilson KL (2006) Multiple roles for emerin: implications for Emery-Dreifuss muscular dystrophy. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 288, 676680.
  • Ishimura A, Ng JK, Taira M, Young SG, Osada S (2006) Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor beta signaling. Development 133, 39193928.
  • Johnson BR, Nitta RT, Frock RL, Mounkes L, Barbie DA, Stewart CL, Harlow E, Kennedy BK (2004) A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Proc. Natl Acad. Sci. USA 101, 96779682.
  • Jung HJ, Coffinier C, Choe Y, Beigneux AP, Davies BS, Yang SH, Barnes RH 2nd, Hong J, Sun T, Pleasure SJ, Young SG, Fong LG (2012) Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA. Proc. Natl Acad. Sci. USA 109, E423E431.
  • Kelley JB, Datta S, Snow CJ, Chatterjee M, Ni L, Spencer A, Yang CS, Cubeñas-Potts C, Matunis MJ, Paschal BM (2011) The defective nuclear lamina in Hutchinson-gilford progeria syndrome disrupts the nucleocytoplasmic Ran gradient and inhibits nuclear localization of Ubc9. Mol. Cell. Biol. 31, 33783395.
  • King CR, Lemmer J, Campbell JR, Atkins AR (1978) Osteosarcoma in a patient with Hutchinson-Gilford progeria. J. Med. Genet. 15, 481484.
  • Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 8, 387398.
  • Kubben N, Voncken JW, Demmers J, Calis C, van Almen G, Pinto Y, Misteli T (2010) Identification of differential protein interactors of lamin A and progerin. Nucleus 1, 513525.
  • Kurpinski K, Lam H, Chu J, Wang A, Kim A, Tsay E, Agrawal S, Schaffer DV, Li S (2010) Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells. Stem Cells 28, 734742.
  • Lai AY, Wade PA (2011) Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nat. Rev. Cancer 11, 588598.
  • Lammerding J, Lee RT (2005) The nuclear membrane and mechanotransduction: impaired nuclear mechanics and mechanotransduction in lamin A/C deficient cells. Novartis Found. Symp. 264, 264273. discussion 273–268.
  • Lammerding J, Schulze P, Takahashi T, Kozlov S, Sullivan T, Kamm R, Stewart C, Lee R (2004) Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J. Clin. Invest. 113, 370378.
  • Lammerding J, Hsiao J, Schulze PC, Kozlov S, Stewart CL, Lee RT (2005) Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells. J. Cell Biol. 170, 781791.
  • Lerner A, Antman KH (2012). Primary and Metastatic Malignant Bone Lesions in: Goldman's Cecil Medicine. 24th edn. Chapter 208, Elsevier Saunders: Philadelphia.
  • Lin ST, Fu YH (2009) miR-23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination. Dis. Model Mech. 2, 178188.
  • Lin F, Morrison JM, Wu W, Worman HJ (2005) MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Hum. Mol. Genet. 14, 437445.
  • Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadinanos J, Lopez-Otin C, Tse HF, Hutchison C (2005) Genomic instability in laminopathy-based premature aging. Nat. Med. 11, 780785.
  • Liu Y, Wang Y, Rusinol AE, Sinensky MS, Liu J, Shell SM, Zou Y (2008) Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A. FASEB J. 22, 603611.
  • Ljungman M, Lane DP (2004) Transcription-guarding the genome by sensing DNA damage. Nat. Rev. Cancer. 4, 727737.
  • Malhas AN, Vaux DJ (2009) Transcription factor sequestration by nuclear envelope components. Cell Cycle 9, 531539.
  • Malhas A, Saunders NJ, Vaux DJ (2010) The nuclear envelope can control gene expression and cell cycle progression via miRNA regulation. Cell Cycle 9, 531539.
  • Manju K, Muralikrishna B, Parnaik VK (2006) Expression of disease-causing lamin A mutants impairs the formation of DNA repair foci. J. Cell Sci. 119, 27042714.
  • Mansharamani M, Wilson KL (2005) Direct binding of nuclear membrane protein MAN1 to emerin in vitro and two modes of binding to barrier-to-autointegration factor. J. Biol. Chem. 280, 1386313870.
  • Maraldi NM, Capanni C, Lattanzi G, Camozzi D, Facchini A, Manzoli FA (2008) SREBP1 interaction with prelamin A forms: a pathogenic mechanism for lipodystrophic laminopathies. Adv. Enzyme Regul. 48, 209223.
  • Marji J, O'Donoghue SI, McClintock D, Satagopam VP, Schneider R, Ratner D, Worman HJ, Gordon LB, Djabali K (2010) Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition. PLoS ONE 5, e11132.
  • Marmiroli S, Bertacchini J, Beretti F, Cenni V, Guida M, De Pol A, Maraldi NM, Lattanzi G (2009) A-type lamins and signaling: the PI 3-kinase/Akt pathway moves forward. J. Cell. Physiol. 220, 553561.
  • Mattout A, Pike BL, Towbin BD, Bank EM, Gonzalez-Sandoval A, Stadler MB, Meister P, Gruenbaum Y, Gasser SM (2011) An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity. Curr. Biol. 21, 16031614.
  • Mattout-Drubezki A, Gruenbaum Y (2003) Dynamic interactions of nuclear lamina proteins with chromatin and transcriptional machinery. Cell. Mol. Life Sci. 60, 20532063.
  • McClintock D, Ratner D, Lokuge M, Owens DM, Gordon LB, Collins FS, Djabali K (2007) The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin. PLoS ONE 2, e1269.
  • Mehta IS, Eskiw CH, Arican HD, Kill IR, Bridger J (2011) Farnesyltransferase inhibitor treatment restores chromosome territory positions and active chromosome dynamics in Hutchinson-Gilford progeria syndrome cells. Genome Biol. 12, R74.
  • Meister P, Towbin BD, Pike BL, Ponti A, Gasser SM (2010) The spatial dynamics of tissue-specific promoters during C. elegans development. Genes Dev. 15, 766782.
  • Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC, Zalewski C, Kim HJ, Solomon B, Brooks BP, Gerber LH, Turner ML, Domingo DL, Hart TC, Graf J, Reynolds JC, Gropman A, Yanovski JA, Gerhard-Herman M, Collins FS, Nabel EG, Cannon ROr, Gahl WA, Introne WJ (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. N. Engl. J. Med. 358, 592604.
  • Meshorer E, Gruenbaum Y (2009) NURD keeps chromatin young. Nat. Cell Biol. 11, 11761177.
  • Mewborn SK, Puckelwartz MJ, Abuisneineh F, Fahrenbach JP, Zhang Y, MacLeod H, Dellefave L, Pytel P, Selig S, Labno CM, Reddy K, Singh H, McNally E (2010) Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation. PLoS ONE 5, e14342.
  • Moir RD, Spann TP, Herrmann H, Goldman RD (2000) Disruption of nuclear lamin organization blocks the elongation phase of DNA replication. J. Cell Biol. 149, 11791192.
  • Montes de Oca R, Shoemaker CJ, Gucek M, Cole RN, Wilson KL (2009) Barrier-to-autointegration factor proteome reveals chromatin-regulatory partners. PLoS ONE 4, e7050.
  • Musich PR, Zou Y (2009) Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A. Aging 1, 2837.
  • Musich PR, Zou Y (2011) DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome. Biochem. Soc. Trans. 39, 17641769.
  • Nili E, Cojocaru1 GS, Kalma Y, Ginsberg D, Copeland NG, Gilbert DJ, Jenkins NA, Berger R, Shaklai S, Amariglio N, Brok-Simoni1 F, Simon AJ, Rechavi G (2001) Nuclear membrane protein, LAP2b, mediates transcriptional repression alone and together with its binding partner GCL (germ cell –less). J. Cell Sci. 114, 32973307.
  • Nitta RT, Smith CL, Kennedy BK (2007) Evidence that proteasome-dependent degradation of the retinoblastoma protein in cells lacking A-type lamins occurs independently of gankyrin and MDM2. PLoS ONE 2, e963.
  • Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, Erdos MR, Blair C, Funke B, Smoot L, Gerhard-Herman M, Machan JT, Kutys R, Virmani R, Collins FS, Wight TN, Nabel EG, Gordon LB (2010) Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of ging. Arterioscler. Thromb. Vasc. Biol. 30, 23012309.
  • Pan D, Estevez-Salmeron LD, Stroschein SL, Zhu X, He J, Zhou S, Luo K (2005) The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines. J. Biol. Chem. 280, 1599216001.
  • Pegoraro G, Kubben N, Wickert U, Göhler H, Hoffmann K, Misteli T (2009) Ageing-related chromatin defects through loss of the NURD complex. Nat. Cell Biol. 11, 12611267.
  • Peric-Hupkes D, van Steensel B (2010) Role of the nuclear lamina in genome organization and gene expression. Cold Spring Harb. Symp. Quant. Biol. 75, 517524.
  • Plasilova M, Chattopadhyay C, Ghosh A, Wenzel F, Demougin P, Noppen C, Schaub N, Szinnai G, Terracciano L, Heinimann K (2011) Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS). PLoS ONE 6, e21433.
  • Puckelwartz MJ, Depreux FF, McNally EM (2011) Gene expression, chromosome position and lamin A/C mutations. Nucleus 2, 162167.
  • Puddu P, Puddu GM, Cravero E, De Pascalis S, Muscari A (2009) The emerging role of cardiovascular risk factor-induced mitochondrial dysfunction in atherogenesis. J. Biomed. Sci. 16, 112.
  • Puente XS, Quesada V, Osorio FG, Cabanillas R, Cadiñanos J, Fraile JM, Ordóñez GR, Puente DA, Gutiérrez-Fernández A, Fanjul-Fernández M, Lévy N, Freije JM, López-Otín C (2011) Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am. J. Hum. Genet. 88, 650656.
  • Rauner M, Sipos W, Goettsch C, Wutzl A, Foisner R, Pietschmann P, Hofbauer LC (2009) Inhibition of lamin A/C attenuates osteoblast differentiation and enhances RANKL-dependent osteoclastogenesi. J. Bone Miner. Res. 24, 7886.
  • Raz V, Vermolen BJ, Garini Y, Onderwater JJ, Mommaas-Kienhuis MA, Koster AJ, Young IT, Tanke H, Dirks RW (2008) The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells. J. Cell Sci. 121, 40184028.
  • Redwood AB, Gonzalez-Suarez I, Gonzalo S (2011) Regulating the levels of key factors in cell cycle and DNA repair: new pathways revealed by lamins. Cell Cycle 10, 36523657.
  • Richards SA, Muter J, Ritchie P, Lattanzi G, Hutchison CJ (2011) The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine. Hum. Mol. Genet. 20, 39974004.
  • Rosen ED, MacDougald OA (2006) Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885896.
  • Sahin E, DePinho RA (2010) Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520528.
  • Sahin E, DePinho RA (2012) Axis of ageing: telomeres, p53 and mitochondria. Nat. Rev. Mol. Cell Biol. 13, 397404.
  • Sahin E, Colla S, Liesa M, Moslehi J, Müller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, Maser RS, Tonon G, Foerster F, Xiong R, Wang YA, Shukla SA, Jaskelioff M, Martin ES, Heffernan TP, Protopopov A, Ivanova E, Mahoney JE, Kost-Alimova M, Perry SR, Bronson R, Liao R, Mulligan R, Shirihai OS, Chin L, DePinho D (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359365.
  • Sasseville AM, Langelier Y (1998) In vitro interaction of the carboxy-terminal domain of lamin A with actin. FEBS Lett. 425, 485489.
  • Scaffidi P, Misteli T (2005) Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat. Med. 11, 440445.
  • Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312, 10591063.
  • Scaffidi P, Misteli T (2008) Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nat. Cell Biol. 10, 452459.
  • Shalev SA, De Sandre-Giovannoli A, Shani AA, Levy N (2007) An association of Hutchinson-Gilford progeria and malignancy. Am. J. Med. Genet. A. 143, 18211826.
  • Shimi T, Butin-Israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA, Shumaker DK, Kosak ST, Chandel NS, Goldman RD (2011) The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 25, 25792593.
  • Shumaker DK, Lee KK, Tanhehco YC, Craigie R, Wilson KL (2001) LAP2 binds to BAF-DNA complexes: requirement for the LEM domain and modulation by variable regions. EMBO J. 20, 17541764.
  • Shumaker DK, Dechat T, Kohlmaier A, Adam DA, Bozovsky MR, Erdos MR, Eriksson M, Goldman AE, Khuon S, Collins FS, Jenuwein T, Goldman RE (2006) Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc. Natl Acad. Sci. USA 103, 87038708.
  • Shumaker DK, Solimando L, Sengupta K, Shimi T, Adam SA, Grunwald A, Strelkov SV, Aebi U, Cardoso MC, Goldman RD (2008) The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication. J. Cell Biol. 181, 269280.
  • Siersbaek R, Nielsen R, Mandrup S (2010) PPARgamma in adipocyte differentiation and metabolism–novel insights from genome-wide studies. FEBS Lett. 584, 32423249.
  • Simon DN, Wilson KL (2011) The nucleoskeleton as a genome-associated dynamic ‘network of networks. Nat. Rev. Mol. Cell Biol. 12, 695708.
  • Simon DN, Zastrow MS, Wilson KL (2010) Direct actin binding to A- and B-type lamin tails and actin filament bundling by the lamin A tail. Nucleus 1, 264272.
  • Simon DN, Domaradzki T, Hofmann WA, Wilson KL (2013) Lamin A tail modification by SUMO1 is disrupted by familial partial lipodystrophy-causing mutations. Mol. Biol. Cell 24, 342350.
  • Soliman MA, Riabowol K (2007) After a decade of study-ING, a PHD for a versatile family of proteins. Trends Biochem. Sci. 32, 509519.
  • Somech R, Shaklai S, Geller O, Amariglio N, Simon AJ, Rechavi G, Gal-Yam EN (2005) The nuclear-envelope protein and transcriptional repressor LAP2beta interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation. J. Cell Sci. 118, 40174025.
  • Spann TP, Goldman AE, Wang C, Huang S, Goldman RD (2002) Alteration of nuclear lamin organization inhibits RNA polymerase II-dependent transcription. J. Cell Biol. 156, 603608.
  • Starr DA (2007) Communication between the cytoskeleton and the nuclear envelope to position the nucleus. Mol. BioSyst. 3, 583589.
  • van Steensel B (2011) Chromatin: constructing the big picture. EMBO J. 30, 18851895.
  • Taimen P, Pfleghaar K, Shimi T, Möller D, Ben-Harush K, Erdos MR, Adam SA, Herrmann H, Medalia O, Collins FS, Goldman AE, Goldman RD (2009) A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization. Proc. Natl Acad. Sci. USA 106, 2078820793.
  • Takano H, Komuro I (2009) Peroxisome proliferator-activated receptor gamma and cardiovascular diseases. Circ. J. 73, 214220.
  • Thomas DM, Carty SA, Piscopo DM, Lee JS, Wang WF, Forrester WC, Hinds PW (2001) The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol. Cell 8, 303316.
  • Towbin DB, González-Aguilera C, Sack R, Gaidatzis D, Kalck V, Meister P, Askjaer P, Gasser SM (2012) Step-wise methylation of histone H3K9 positions chromosome arms at the nuclear periphery in C. elegans embryos. Cell 150, 934947.
  • Trigueros-Motos L, Gonzalez JM, Rivera J, Andres V (2011) Hutchinson-Gilford progeria syndrome, cardiovascular disease and oxidative stress. Front. Biosci. 3, 12851297.
  • Van Berlo JH, Voncken JW, Kubben N, Broers JL, Duisters R, van Leeuwen RE, Crijns HJ, Ramaekers FC, Hutchison CJ, Pinto YM (2005) A-type lamins are essential for TGF-beta1 induced PP2A to dephosphorylate transcription factors. Hum. Mol. Genet. 14, 28392849.
  • Varela I, Pereira S, Ugalde AP, Navarro CL, Suárez MF, Cau P, Cadiñanos J, Osorio FG, Cobo J, de Carlos F, Lévy N, Freije JMP, López-Otín C (2008) Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat. Med. 14, 767772.
  • Verstraeten VL, Ji JY, Cummings KS, Lee RT, Lammerding J (2008) Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell 7, 383393.
  • Visa N, Percipalle P (2010) Nuclear functions of actin. Cold Spring Harb. Perspect. Biol. 2, a000620.
  • Viteri G, Chung YW, Stadtman ER (2010) Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients. Mech. Aging Dev. 131, 28.
  • Wilson KL, Foisner R (2010) Lamin-binding proteins. Cold Spring Harb. Perspect. Biol. 2, a000554.
  • Zhang YQ, Sarge KD (2008) Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies. J. Cell Biol. 182, 3539.
  • Zhang J, Lian Q, Zhu G, Zhou F, Sui L, Tan C, Mutalif RA, Navasankari R, Zhang Y, Tse HF, Stewart CL, Colman A (2011) A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell. Stem Cells. 8, 3145.
  • Zullo JM, Demarco IA, Piqué-Regi R, Gaffney DJ, Epstein CB, Spooner CJ, Luperchio TR, Bernstein BE, Pritchard JK, Reddy KL, Singh H (2012) DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149, 14741487.
  • Zwerger M, Ho CY, Lammerding J (2011) Nuclear mechanics in disease. Annu. Rev. Biomed. Eng. 15, 397428.