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Abbreviations
AP-1

activator protein 1

APAP

acetaminophen

GSTs

glutathione S-transferases

GSTP1

(glutathione S-transferase pi 1

HAT

histone acetylase

opn

osteopontin

Tg

transgenic

TPA

12-O-tetradecanoylphorbol- 13-acetate

TRE

TPA responsive element.

Activator protein 1 (AP-1) proteins, such as Fos and Jun, are prototypic oncogenes regulating cell proliferation, differentiation, and cell transformation in development and in adults in various organs. The dimeric transcription factor, composed of basic region/leucine zipper proteins, is conserved from flies to humans and is activated by various kinds of stresses. Numerous studies have revealed that AP-1 exerts its functions in a cell context- and component-dependent manner.[1, 2] In mammals, the most studied AP-1 proteins are the family members of Jun, including c-Jun, JunB, and JunD, and Fos, including c-Fos, FosB, Fra1, and Fra2 (Fig. 1A). Whereas the Jun proteins exist as homo- and heterodimers, the Fos proteins, which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA-binding activity. AP-1 recognizes the DNA-binding site, the TPA responsive element (TRE; TCACTCA; Fig. 1A), so called because it is strongly induced by the tumor promoter, 12-O-tetradecanoylphorbol- 13-acetate (TPA). In addition to tumor promoters, DNA binding of the AP-1 complex to the TRE sequence is rapidly induced by growth factors, cytokines, oncoproteins, and bacterial products, which are implicated in the proliferation, survival, differentiation, and transformation of cells.[3]

image

Figure 1. AP-1 transcription factors. (A) AP-1 proteins consist of either Jun homodimers or Jun/Fos heterodimers that bind to the TRE. (B) The c-Jun/Fra-1 heterodimer is activated by the three-step mitogen-activated protein kinase phosphorylation cascade, binds to the TRE, recruits a HAT, and induces transcription of genes, such as onp and gstp1.

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AP-1 is regulated at multiple levels, such as at the level of transcription, messenger RNA turnover, protein stability, and interactions with other transcription factors. Moreover, activity of AP-1 is also modulated by post-translational modifications, for example, by upstream kinases such as Jun N-terminal kinases and early response kinases (Fig. 1B). For example, phosphorylated c-Jun and phosphorylated FRA-1 form a heterodimer, bind to the TRE, recruit a histone acetyltransferase (HAT), and induce transcription of target genes (Fig. 1B).

The AP1s are important transcription factors in multiple pathways in liver physiology, such as hepatic regeneration, and disease pathogenesis, such as hepatocellular carcinogenesis, nonalcoholic fatty liver disease, and liver fibrosis.[4, 5]

Fra-1 in Liver Fibrosis

  1. Top of page
  2. Fra-1 in Liver Fibrosis
  3. Fra-1 in Detoxification
  4. References

Previous studies had demonstrated that overexpression of either of the Fos-related proteins, Fra-1 or Fra-2, resulted in generalized tissue fibrosis in mice, particularly in the lung and liver.[6, 7] The current study[8] generated novel transgenic (Tg) mouse models harboring switchable, general or hepatocyte-specific, Fra-1 (the fosl1 gene), and, investigated for the first time, the role of Fra-1 in liver disease using loss-of-function animals. Broad Fra-1 expression in adult Fra-1tetON mice largely recapitulated the phenotypes observed in Fra-1Tg mice with a randomly integrated transgene.[1] Specifically, mutant mice developed periportal fibrosis, a ductular reaction, cytokine dys-regulation, and inflammatory cell infiltrate. An advantage of this new model is the ability to switch off transgene expression. Doxycycline withdrawal in Fra-1tetON mutant mice led to decreased cholestasis and regression of liver fibrosis. Such “transgene addiction” demonstrates the requirement for Fra-1 to maintain the cholestasis phenotype and provides a rationale for experimentally addressing the functional relevance of Fra-1 in clinical cholestasis and liver fibrosis, identifying Fra-1's transcriptional targets, and examining its role in regression of fibrosis and elimination of fibrogenic myofibroblasts.

Through a careful analysis of Fra-1 knockout and Fra-1 hepatocyte-specific and general overexpressing mice, combined with chromatin and transcriptional analysis, relevant Fra-1-regulated genes were identified. These included induction of the fibrogenic gene, osteopontin (opn), and inhibition of the antifibrotic gene, cxcl9, in hepatocytes. Interestingly, overexpression of Fra-1 only in hepatocytes is not sufficient to induce cholestasis and liver fibrosis, suggesting that Fra-1 overexpression in other cells, such as cholangiocytes or myofibroblasts, is required for cholestasis and fibrosis. Further studies are required to identify the origin and fate of the fibrogenic myofibroblasts in this reversible model of cholestatic liver injury and fibrosis.[9]

Fra-1 in Detoxification

  1. Top of page
  2. Fra-1 in Liver Fibrosis
  3. Fra-1 in Detoxification
  4. References

Cholestasis and hepatotoxicity are counteracted by protective mechanisms, including modulating transport and detoxification of bile acids and xenobiotics. For example, glutathione S-transferases (GSTs) catalyze the conjugation of toxic compounds with reduced glutathione, thus facilitating their biliary secretion. In additional experiments, the overexpressing Fra-1 mutant mice were protected from 3,5-diethoxycarbonyl-1,4-dihydrocollidine- and acetaminophen (APAP)-induced liver injury. The proposed mechanism is that GSTP1 (glutathione S-transferase pi 1) is up-regulated by the AP-1 transcription factor, cJun/Fra-1, thus increasing the detoxification of APAP. This effect is unique to Fra-1, because Fra-1-deficient mice had increased sensitivity to APAP hepatotoxicity, whereas Fra-2-overexpressing mice were not protected. Further elucidation of the genetic and cellular targets of Fra-1 that produce hepatoprotection in some situations, but increased hepatic injury in others, should provide new insights into the complex role of AP-1 in liver disease and the potential role of inhibitors of the signaling pathway in the treatment of specific liver diseases.

  • David A. Brenner, M.D.

  • University of California San Diego

  • La Jolla, CA

References

  1. Top of page
  2. Fra-1 in Liver Fibrosis
  3. Fra-1 in Detoxification
  4. References