Expression of Siah-2, a vertebrate homologue of Drosophila sina, in germ cells of the mouse ovary and testis

Della, Neil G.; Bowtell, David D.; Beck, Felix

doi:10.1007/bf00318499

Cited by 14 publications

(10 citation statements)

References 40 publications

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“…It is significant that chromosome segregation defects are seen only during spermatogenesis in Siah1a Ϫ/Ϫ mice. As Siah2 expression is detected only in postmeiotic spermatocytes (8) and the Siah1b gene resides on the X chromosome and is thus likely to be silenced by X inactivation during spermatogenesis (17), it is possible that this setting reflects a true Siah gene loss-of-function phenotype. To begin to examine this possibility, we have analyzed the cell cycle properties of MEFs lacking Siah1a, Siah1b, or Siah2 or lacking both Siah2 and Siah1a.…”

Section: Vol 22 2002 Normal P53 Function In Cells Deficient For Siamentioning

confidence: 99%

Normal p53 Function in Primary Cells Deficient for Siah Genes

Frew

Dickins

Cuddihy

et al. 2002

Molecular and Cellular Biology

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Overexpression studies have suggested that Siah1 proteins may act as effectors of p53-mediated cellular responses and as regulators of mitotic progression. We have tested these hypotheses using Siah gene knockout mice. Siah1a and Siah1b were not induced by activation of endogenous p53 in tissues, primary murine embryonic fibroblasts (MEFs) or thymocytes. Furthermore, primary MEFs lacking Siah1a, Siah1b, Siah2, or both Siah2 and Siah1a displayed normal cell cycle progression, proliferation, p53-mediated senescence, and G 1 phase cell cycle arrest. Primary thymocytes deficient for Siah1a, Siah2, or both Siah2 and Siah1a, E1A-transformed MEFs lacking Siah1a, Siah1b, or Siah2, and Siah1b-null ES cells all underwent normal p53-mediated apoptosis. Finally, inhibition of Siah1b expression in Siah2 Siah1a double-mutant cells failed to inhibit cell division, p53-mediated induction of p21 expression, or cell cycle arrest. Our loss-of-function experiments do not support a general role for Siah genes in p53-mediated responses or mitosis.p53 acts as a tumor suppressor by inducing cell cycle arrest, apoptosis, and senescence in response to cellular stresses such as DNA damage or oncogene activation. These effects are mediated largely through the function of p53 as a transcriptional activator or repressor (5, 25). A diverse range of p53 target genes have been identified, for example, p21, an important mediator of G 1 phase cell cycle arrest and cellular senescence (10), and several proapoptotic genes including Noxa and Bax (53). However, understanding of the full range of p53 effectors is incomplete and it is likely that multiple signaling pathways are involved in determining cellular responses to p53 activation.Recent studies have proposed that Siah1, a member of the Siah family of E3 ubiquitin ligases, may act as a downstream effector of p53. Overexpression of p53 induces the transcriptional activation of Siah1 family genes in a variety of mammalian cell lines (1,20,32,35,43,44,47), and overexpression of Siah1 can mimic the effects of p53 activation and induce cell cycle arrest or apoptosis (37,43,44).A molecular mechanism by which Siah1 proteins may mediate p53 function has been proposed. Human SIAH1 functions as a component of an E3 ubiquitin ligase complex including Siah-interacting protein, Skp1, and the F-box protein Ebi, which is proposed to target ␤-catenin for ubiquitin-mediated degradation in response to activation of p53 (32,36,42). Importantly, overexpression of either p53 or SIAH1 can induce ␤-catenin degradation, and this is blocked by coexpression of an N-terminally truncated SIAH1 protein lacking the RING domain. By this model, p53-mediated induction of SIAH1 following DNA damage induces degradation of ␤-catenin independently of the GSK3␤-mediated degradation pathway. Since overexpression of ␤-catenin promotes cell cycle progression and inhibits cell cycle arrest induced by gamma irradiation (41), SIAH1-mediated ␤-catenin degradation may contribute to p53-dependent cell cycle arrest. Interestingly, accumulatio...

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Section: Vol 22 2002 Normal P53 Function In Cells Deficient For Siamentioning

confidence: 99%

Normal p53 Function in Primary Cells Deficient for Siah Genes

Frew

Dickins

Cuddihy

et al. 2002

Molecular and Cellular Biology

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“…Its function is related to the correct integration of signal transduction downstream of the tyrosine kinase receptor sevenless and Ras-1 (2,3). Its murine homologues (mmsiahl and mmsiah2) are widely expressed during fetal development as well in the adult (4,5). The expression of mmsiah2 is increased more specifically during development of the olfactory epithelium, retina, forebrain, and proliferating cartilage.…”

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confidence: 99%

Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression.

Nemani

Linares-Cruz

Bruzzoni‐Giovanelli

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

113

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Developmentally regulated genes in Drosophila, which are conserved through evolution, are potential candidates for key functions in biological processes such as cell cycle, programmed cell death, and cancer. We report cloning and characterization of the human homologue of the Drosophila seven in absentia gene (HUMSIAH), which codes for a 282 amino acids putative zinc finger protein. HUMSIAH is localized on human chromosome 16ql2-ql3. This gene is activated during the physiological program of cell death in the intestinal epithelium. Moreover, human cancer-derived cells selected for suppression of their tumorigenic phenotype exhibit constitutively elevated levels of HUMSIAH mRNA. A similar pattern of expression is also displayed by the p2lwan. These results suggest that mammalian seven in absentia gene, which is a target for activation by p53, may play a role in apoptosis and tumor suppression.

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“…We generated polyclonal and monoclonal antibodies that recognize recombinant and overexpressed Siah2 in Western blotting and immunoprecipitation (17), but these were of insufficient sensitivity to detect endogenous Siah2 protein in any tissue or cell line derived from wild-type mice (data not shown). To further confirm loss of Siah2 expression, we performed in situ hybridization to developing ovarian follicles, a site where Siah2 mRNA is normally strongly expressed (7). When an antisense riboprobe located 3Ј of the insertion site was used for this analysis we found that expression of Siah2 mRNA was lost in mutant mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…High Siah1 expression in testes (7) correlates with the spermatogenic phenotype in Siah1a mutant mice (9). In contrast, sites of high Siah2 expression, including ovaries, testes, cartilage, and retinal and olfactory neuroepithelia (7,8), are histologically normal in Siah2 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

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Generation and Analysis of Siah2 Mutant Mice

Frew

Hammond

Dickins

et al. 2003

Molecular and Cellular Biology

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Siah proteins function as E3 ubiquitin ligase enzymes to target the degradation of diverse protein substrates. To characterize the physiological roles of Siah2, we have generated and analyzed Siah2 mutant mice. In contrast to Siah1a knockout mice, which are growth retarded and exhibit defects in spermatogenesis, Siah2 mutant mice are fertile and largely phenotypically normal. While previous studies implicate Siah2 in the regulation of TRAF2, Vav1, OBF-1, and DCC, we find that a variety of responses mediated by these proteins are unaffected by loss of Siah2. However, we have identified an expansion of myeloid progenitor cells in the bone marrow of Siah2 mutant mice. Consistent with this, we show that Siah2 mutant bone marrow produces more osteoclasts in vitro than wild-type bone marrow. The observation that combined Siah2 and Siah1a mutation causes embryonic and neonatal lethality demonstrates that the highly homologous Siah proteins have partially overlapping functions in vivo.

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Expression of Siah-2, a vertebrate homologue of Drosophila sina, in germ cells of the mouse ovary and testis

Cited by 14 publications

References 40 publications

Normal p53 Function in Primary Cells Deficient for Siah Genes

Normal p53 Function in Primary Cells Deficient for Siah Genes

Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression.

Generation and Analysis of Siah2 Mutant Mice

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