Nucleobindin 2 (NUCB2) in human breast carcinoma as a potent prognostic factor
Estrogens contribute to the progression of human breast carcinoma through interaction with estrogen receptor (ER), which activates transcription of target genes by binding estrogen responsive elements (ERE). Although most ER-positive breast carcinomas respond to endocrine therapy, some of these carcinomas develop resistance to endocrine therapy. To further elucidate the molecular mechanisms of estrogens, Suzuki and colleagues studied the expression profile of genes containing ERE in ER-positive breast carcinoma tissues. Microarray data revealed an association between recurrence and nucleobindin 2 (NUCB2), a gene not previously examined in relation to breast carcinoma. In vitro studies demonstrated that estradiol upregulated NUCB2 in ER-positive MCF-7 cells. NUCB2 immunoreactivity was found in 48% of breast carcinoma tissues and was an independent prognostic factor for patients. Additional studies revealed that NUCB2 significantly increased cell proliferation, migration and invasion in both MCF-7 and ER-negative SK-BR-3 cells. The authors suggest that NUCB2 plays an important role in the metastasis of breast carcinoma and that NUCB2 status is a potent prognostic factor in human breast cancer.
TSC-22 is a negative-feedback regulator of Ras/Raf signaling: Implications for tumorigenesis
In this issue, Nakamura and colleagues report a novel mechanism to regulate the expression of transforming growth factor-β (TGF-β)-stimulated clone-22 (TSC-22), a putative tumor suppressor. Previously, the authors reported that TSC-22, also known as TSC22D1-2, was upregulated by an active mutant of FMS-like tyrosine kinase-3 (Flt3). The authors now describe that TSC-22 works as a tumor suppressor by inhibiting Ras/Raf signaling. Ras/Raf activation upregulated TSC-22, yet this upregulation was inhibited by concurrent STAT5 activation. Ras/Raf activation also caused nuclear translocation of TSC-22, a short isoform of TSC-22 domain family 1 (TSC22D1), but not TSCD1-1, a long splice variant. Upregulation and nuclear translocation of TSC-22 played an important role in the feedback suppression of Ras/Raf signaling. TSC22D1-deficient mice were susceptible to tumorigenesis in a mouse model of chemically induced liver tumors with active mutations of Ras/Raf. The authors conclude that TSC-22 is a novel negative-feedback regulator of Ras/Raf signaling.
Serine/threonine kinase Melk regulates proliferation and glial differentiation of retinal progenitor cells
Serine/threonine kinase Melk is known to play a role in carcinogenesis. In previous studies analyzing the function of Melk in embryogenesis, Saito and colleagues cloned zebrafish Melk and found that morpholino-based downregulation of Melk caused severe anemia and microphthalmia. The latter result suggested a role of Melk in retinal development, a role not previously investigated. Saito and colleagues now report further studies of Melk in a mouse model. Gain- and loss-of-function analyses of Melk in mouse retinas demonstrated that the level of Melk in retinal progenitor cells positively correlated with their proliferative activities. Differentiation of retinal progenitor cells into subtypes of retinal neurons was not significantly affected. However, the absence of Melk extended the process formation of Müller glia, suggesting that Melk affects the morphological differentiation of retinal cells. The authors suggest that Melk is required for proper proliferation of retinal progenitors and might play multiple roles in retinal development in vertebrates.