Generation and Analysis of <i>Siah2</i> Mutant Mice

Frew, Ian J.; Hammond, Vicki E.; Dickins, Ross A.; Quinn, J; Walkley, Carl R.; Sims, Natalie A.; Schnall, Ralf; Della, Neil G.; Holloway, Andrew; Digby, Matthew R.; Janes, Peter W.; Tarlinton, David M.; Purton, Louise E.; Gillespie, Matthew T.; Bowtell, David D.L.

doi:10.1128/mcb.23.24.9150-9161.2003

Cited by 66 publications

(73 citation statements)

References 61 publications

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“…The generation of double knockout animals for the mouse homo- logues of Siah, Siah1a and Siah2, has demonstrated an essential role in embryonic development, whereas the individual knockout phenotypes are less severe (25)(26)(27)(28). Currently, little is known about the regulation of Siah, but it appears that hypoxia, Wnt 5a, and p53 are capable of up-regulating Siah mRNA and protein expression (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Frasor

Danes

Funk

et al. 2005

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

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C ellular activity is precisely regulated by a finely tuned balance between coactivator and corepressor proteins that control transcriptional networks during development and in normal and cancerous states (1). The corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) play crucial roles in transcriptional repression by multiple classes of transcription factors, including some nuclear hormone receptors. Repression by N-CoR and SMRT results from their association with large histone deacetylase complexes, which lead to histone deacetylation, altered chromatin structure, and decreased gene transcription (reviewed in ref. 2). Although few studies have demonstrated that N-CoR expression is regulated at the level of gene transcription, several examples of posttranslational regulation of N-CoR expression and activity have been described. Recent studies have shown that N-CoR interaction with transcription factors, such as NF-B and estrogen receptor (ER), can be reduced through translocation of N-CoR out of the nucleus and into the cytoplasm (3-5). N-CoR has also been shown to be regulated by ubiquitin-mediated protein degradation through an interaction with the E3 ubiquitin ligase Siah2, a mammalian homolog of Drosophila seven in absentia (Sina), which leads to the ubiquitination and degradation of N-CoR by the 26S proteasome (6).The majority of estrogen's effects on its numerous target tissues are mediated by its two receptors, ER␣ and ER␤, which act primarily as ligand-dependent transcription factors. Upon binding to its ligand, the ER associates with DNA either directly at estrogen response elements or through tethering to other transcription factors, leading to the recruitment of transcriptional coregulators and chromatin-modifying complexes and the regulation of gene expression (7). We and others (8-17) have used microarray gene expression profiling to identify estrogen target genes in breast cancer cells, where estrogen has been shown to stimulate proliferation and suppress apoptosis through the regulation of multiple genes. These studies have demonstrated that, as expected, estrogen up-regulates many cell-cycle regulators, growth factors, and antiapoptotic genes but also down-regulates a number of cell-cycle inhibitors and proapoptotic genes.Estrogen also regulates the mRNA expression of important transcriptional regulators, both transcription factors and transcriptional coactivators and corepressors (12). Evidence supporting the idea that 17␤-estradiol (E2) is capable of regulating the expression of coregulators has grown in the past few years. For example, this hormone has been shown to up-regulate mRNA levels for the corepressors RIP140 (12, 18), SHP (19), and SHARP (20) and also to down-regulate mRNA levels for the coactivators 21). In addition to the regulation of mRNA for some coregulators, the activity of these proteins can be modulated by hormone by changing the protein's state of phosphorylation, as observed for the coactivator SRC3͞AIB1...

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Section: Discussionmentioning

confidence: 99%

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Frasor

Danes

Funk

et al. 2005

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

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“…PyMT-Siah2 À/À and PyMT-WT mice were generated by crossing C57Bl/6 Siah2 À/À mice (20) with C57Bl/6 PyMTtransgenic mice (kindly provided by Carol MacLeod and Lionel Hebbard, University of California, San Diego, San Diego, CA). All procedures involving mice were conducted in accordance with NHMRC regulations on the use and care of experimental animals and were approved by the Peter MacCallum Cancer Centre Animal Ethics Committee.…”

Section: Animalsmentioning

confidence: 99%

Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy

et al. 2012

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Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1a . In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2À/À genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1a, expression of angiogenic factors was decreased in Siah2tumors. Blood vessel normalization in Siah2 À/À tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1a-mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy.

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“…Other investigators have reported that the E3 ligase activity of TRAF2 regulates TNF-␣-mediated activation of both NF-B and JNK through ubiquitination of RIP1 and JNK. 40,41,[43][44][45] Although we found that TRAF2 co-precipitates with JAB1, we were unable to demonstrate co-precipitation of RIP1 with JAB1 using a tech- were cultured for 48 hours and lysed using immunoprecipitation lysate buffer (Roche). Aliquots of 1 mg of the total protein lysates were immunoprecipitated with a polyclonal anti-Jab1 antibody.…”

Section: Discussionmentioning

confidence: 97%

JAB1 Determines the Response of Rheumatoid Arthritis Synovial Fibroblasts to Tumor Necrosis Factor-α

Wang

Liu

et al. 2006

The American Journal of Pathology

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Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)-␣ stimulation. Here, we show that JAB1 is a critical regulator of the TNF-␣-mediated anti-apoptosis pathways in RA FLSs. We found that knockdown of JAB1 using small interfering (si)RNA led to restoration of the TNF-␣-induced apoptosis response, reduction of nuclear factor-B activity, delayed degradation of IB-␣, and inhibited phosphorylation of JNK. Analysis of the interactions of JAB1 by reciprocal co-immunoprecipitations and confocal microscopy revealed that JAB1 interacts with TNF receptor-associated-factor 2 (TRAF2). The generation of the antiapoptotic signal on binding of TNF-␣ to the TNF receptor (TNFR)1 has been shown to be associated with the recruitment of TRAF2 to the TNFR1 in a process that requires ubiquitination of TRAF2 with lysine-63-linked polyubiquitin chains. We found that TNF-␣ stimulation of JAB1 siRNA-transfected RA FLSs failed to stimulate ubiquitination of TRAF2. Thus, we conclude that JAB1-regulated ubiquitination of TRAF2 is a novel mechanism whereby TNF-␣ can induce antiapoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-B

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Generation and Analysis of Siah2 Mutant Mice

Cited by 66 publications

References 61 publications

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy

JAB1 Determines the Response of Rheumatoid Arthritis Synovial Fibroblasts to Tumor Necrosis Factor-α

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