Siah Proteins: Novel Drug Targets in the Ras and Hypoxia Pathways

House, Colin M.; Möller, Andreas; Bowtell, David D.L.

doi:10.1158/0008-5472.can-09-1676

Cited by 78 publications

(87 citation statements)

References 36 publications

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“…For example, Zyxin has been shown to exert oncogenic activities by facilitating cell migration in melanoma cells (38,39), but it can also act as a tumor suppressor in Ewing carcinoma and prostate cancer cells (32,33). Similar oncogenic versus tumor suppressive activities have been attributed to the ubiquitin ligase Siah-1 (40,41). Because our results here demonstrate that Zyxin and Siah-1 interact and, furthermore, that Zyxin modulates Siah-1 dimerization and thereby presumably its activity, it is tempting to speculate that increased Zyxin levels, such as in case of DNA damage, contribute to uncoupling the ubiquitin ligase Siah-1 from its substrates.…”

Section: Discussionmentioning

confidence: 99%

Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis

et al. 2011

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HIPK2 activates the apoptotic arm of the DNA damage response by phosphorylating tumor suppressor p53 at serine 46. Unstressed cells keep HIPK2 levels low through targeted polyubiquitination and subsequent proteasomal degradation. Here we identify the LIM domain protein Zyxin as a novel regulator of the HIPK2-p53 signaling axis in response to DNA damage. Remarkably, depletion of endogenous Zyxin, which colocalizes with HIPK2 at the cytoskeleton and in the cell nucleus, stimulates proteasome-dependent HIPK2 degradation. In contrast, ectopic expression of Zyxin stabilizes HIPK2, even upon enforced expression of its ubiquitin ligase Siah-1. Consistently, Zyxin physically interacts with Siah-1, and knock-down of Siah-1 rescues HIPK2 expression in Zyxin-depleted cancer cells. Mechanistically, our data suggest that Zyxin regulates Siah-1 activity through interference with Siah-1 dimerization. Furthermore, we show that endogenous Zyxin coaccumulates with HIPK2 in response to DNA damage in cancer cells, and that depletion of endogenous Zyxin results in reduced HIPK2 protein levels and compromises DNA damage-induced p53 Ser46 phosphorylation and caspase activation. These findings suggest an unforeseen role for Zyxin in DNA damage-induced cell fate control through modulating the HIPK2-p53 signaling axis. Cancer Res; 71(6); 2350-9. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis

et al. 2011

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“…Upon these findings, we speculate that downstream factors of Siah1 other than HIF1α may affect tumour progression. Siah was initially identified as a tumour suppressor gene [12], although recent studies have shown that knock-down of Siah by shRNA could significantly impede lung and pancreatic tumour growth in vitro and in vivo, indicating that expression of Siah itself promotes tumour growth [9,13,23]. Another study in breast cancer also showed that increased Siah expression was related to the aggressiveness of breast cancers [24].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, understanding the molecular mechanisms that regulate Siah expression will likely provide new insights into the pivotal function of Siah in cancer biology and should contribute to novel anti-cancer strategies [12,13,25]. The relationship between Siah1 and HIF1α expression and patient prognosis was examined by Kaplan-Meier analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Siah-family proteins are the human homologues of seven-in-absentia, a conserved RING finger E3 ubiquitin ligase and essential downstream component of the Drosophila Ras signaling pathway. Two homologues, Siah1 and Siah2, have been shown to be involved in the response to DNA damage, the hypoxic response, inflammation, and several oncogenic signals including those propagated by Ras and epidermal growth factor receptor (EGFR) [10][11][12][13]. To date, few studies have addressed the role of Siah expression in cancer, and there has been no consensus as to the biologic significance of such expression [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

et al. 2013

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(T. Yoshizaki). Keywords:seven-in-absentia homologue 1 (Siah1) hypoxia-inducible factor 1 alpha (HIF1α) latent membrane protein 1 (LMP1) Epstein-Barr virus (EBV) nasopharyngeal carcinoma ABSTRACT Nasopharyngeal carcinoma (NPC) is an EBV-associated cancer. We analysed Siah1 expression as well as LMP1 and HIF1α expression by immuno-histochemical staining in 74 NPC biopsy specimens and found that the expression of Siah1 was significantly correlated with advanced tumour status and stage. Moreover, Siah1-positive and HIF1α-positive cases had significantly worse prognoses. The expression score for LMP1 was remarkably correlated with that of Siah1, whereas there was little correlation between LMP1 expression and the other markers evaluated. This is the first study to evaluate the pattern and clinical significance of Siah1 and HIF1α expression in NPC, and such an evaluation is valuable for identifying those patients at a high risk for a poor prognosis.

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“…Values are means ± SEM run in triplicates; letters indicate significant differences between treatment groups (P \ 0.05) conserved E3 ubiquitin ligase, sharing 76 % sequence homology. Human SIAH1 and SIAH2 have overlapping functions and recognize similar substrates (House et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Growth factor TGF-β induces intestinal epithelial cell (IEC-6) differentiation: miR-146b as a regulatory component in the negative feedback loop

2012

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TGF-b is a potent pleiotropic factor that promotes small intestinal cell differentiation. The role of microRNAs in the TGF-b induction of intestinal epithelial phenotype is largely unknown. We hypothesized that microRNAs are functionally involved in TGF-b-induced intestinal cell growth. In this study, TGF-b caused a morphological change of IEC-6 cells and stimulated expression of the epithelial cell markers alkaline phosphatase, villin, and aminopeptidase N. By global microRNA profiling during TGF-b-induced intestinal crypt cell (IEC-6) differentiation, we identified 19 differentially expressed microRNAs. We showed by real-time Q-PCR that miR-146b expression increased rapidly after TGF-b treatment; sequence analysis and in vitro assays revealed that miR146b targets SIAH2, an E3 ubiquitin ligase, with decreased protein expression upon IEC-6 cell differentiation. Transfection of miR-146b inhibitor before TGF-b treatment blocked the down-regulation of SIAH2 in response to TGF-b. Moreover, SIAH2 over-expression during TGF-b treatment caused a significant decrease in Smad7 protein expression in IEC-6 cells. Furthermore, activation of the ERK1/2 pathway is active in the up-regulation of miR146b by TGF-b. These findings suggest a novel mechanism whereby TGF-b signaling during IEC-6 cell differentiation may be modulated in part by microRNAs, and we propose a key role for miR-146b in the homeostasis of growth factor TGF-b signaling through a negative feedback regulation involving down-regulation of SIAH2 repressed Smad7 activities.

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Siah Proteins: Novel Drug Targets in the Ras and Hypoxia Pathways

Cited by 78 publications

References 36 publications

Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis

Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis

Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

Growth factor TGF-β induces intestinal epithelial cell (IEC-6) differentiation: miR-146b as a regulatory component in the negative feedback loop

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