TIN2 Stability Is Regulated by the E3 Ligase Siah2

Bhanot, Monica; Smith, Susan

doi:10.1128/mcb.06227-11

Cited by 25 publications

(21 citation statements)

References 58 publications

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“…SIAH1 and SIAH2 targeting siRNAs markedly decreased endothelial expression of SIAH1 and SIAH2 proteins to 39.3 ± 9.6% and 58.6 ± 3.0% of control, respectively (Fig. 4 A, B, D, and E), similar to what was shown in other cell lines (19,20). Intriguingly, SIAH1 or SIAH2 was able to compensate for each other when one was suppressed, because RNAi for SIAH1 led to up-regulated SIAH2 by 1.37 ± 0.11-fold (Fig.…”

Section: No Donor Increases Protein Abundance Of DCC In Endothelial Csupporting

confidence: 86%

Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO

Wang

et al. 2015

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

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Deleted in colorectal cancer (DCC), a large transmembrane receptor of netrin-1, is critical for mediating netrin-1's cardioprotective function. In the present study we investigated novel mechanisms underlying netrin-1-induced, rapid, and feed-forward up-regulation of DCC, which is believed to sustain nitric oxide (NO) production to potentiate cardioprotection. Intriguingly, NO markedly reduced expression of the E3 ubiquitin ligase seven in absentia homolog (SIAH) that is specific for regulation of protesome-dependent DCC degradation, resulting in accumulation of DCC. The two SIAH isoforms compensate for each other when one is repressed; inhibition of both SIAH1 and SIAH2 using combined siRNAs significantly reduced infarct size while improving cardiac function after ischemia/reperfusion injury of the heart. This effect was absent in DCC-deficient mice. Moreover, in vivo RNAi inhibition of SIAH1/2 further augmented netrin-1's cardioprotective function. In summary, these data identify a novel therapeutic target of SIAH in facilitating NO/netrin-1-dependent cardioprotection, using the DCC receptor. Combination of netrin-1 and SIAH RNAi may prove to be a substantially effective therapy for myocardial infarction.eleted in colorectal cancer (DCC), a single transmembrane receptor of netrin-1, was first discovered in 1990 during the search for candidate tumor suppressor genes in chromosome 18q (1). At present DCC is known to play important roles in the following biological processes: guidance of developing axons (2, 3), conditional control of apoptosis (4), tumorigenesis (5), and angiogenesis (6, 7). DCC-dependent production of nitric oxide (NO) mediates angiogenic responses of endothelial cells (6). We have recently identified a novel and robust effect of netrin-1 in cardioprotection (8, 9). Netrin-1 induces cardioprotection against ischemia/reperfusion (I/R) injury both ex vivo and in vivo, which is mediated by DCC/ERK1/2/eNOS/NO-dependent protection of cardiomyocytes from necrosis and apoptosis, mediated by NOdependent attenuation of oxidative stress and preservation of mitochondrial function (8-10). A deficiency of DCC abolished the protective effects of netrin-1 against cardiac I/R injury, implying a crucial role of DCC in mediating netrin-1-induced cardioprotection (8, 10).Although it is a large transmembrane protein, DCC protein abundance was significantly up-regulated by netrin-1 in I/Rinjured heart within a very short time of 2 h (8). Intriguingly, the DCC accumulation induced by netrin-1 was attenuated by the NOS inhibitor L-NAME, implicating an NO-dependent mechanism (8). This NO-DCC feed-forward regulation, in addition to the initial DCC/ERK1/2/eNOS/NO pathway, may be extremely beneficial in potentiating netrin-1-dependent cardioprotection. It is possible that a proteasome dependent mechanism was involved in this quick action of protein regulation. Protein ubiquitination plays a key role in determining the half-life of proteins in mammalian cells. In ubiquitin-proteasome systems, E3 ubiquitin ligases recogniz...

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Section: No Donor Increases Protein Abundance Of DCC In Endothelial Csupporting

confidence: 86%

Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO

Wang

et al. 2015

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

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“…Two components of shelterin complex, TRF2 and TIN2 were reported as Siah-interacting proteins (23, 74). Cellular senescence is associated with reduced expression of TRF2 and increased expression of Siah1.…”

Section: Downstream: Emerging Roles For Siah Ligases In Neuronal Funcmentioning

confidence: 99%

Regulators and Effectors of Siah Ubiquitin Ligases

Kim

Scortegagna

et al. 2013

Cell Biochem Biophys

115

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The Siah ubiquitin ligases are members of the RING finger E3 ligases. The Siah E3s are conserved from fly to mammals. Primarily implicated in cellular stress responses, Siah ligases play a key role in hypoxia, through the regulation of HIF-1α transcription stability and activity. Concomitantly, physiological conditions associated with varying oxygen tension often highlight the importance of Siah, as seen in cancer and neurodegenerative disorders. Notably, recent studies also point to the role of these ligases in fundamental processes including DNA damage response, cellular organization and polarity. This review summarizes the current understanding of upstream regulators and downstream effectors of Siah2.

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“…Specifically, both wild-type and AA Flag-TIN2 co-immunoprecipitated with the known TIN2-interacting proteins TRF1 and TPP1 (Figure S4). Although TIN2 can be ubiquitinated [31], the levels of wild-type and AA Flag-TIN2 protein after cells were treated with cycloheximide were nevertheless similar (Figure S5). Even though TIN2 can localize to mitochondria [32], the wild-type as well as the S295A, S330A and AA mutant versions of GFP-tagged TIN2 exhibited similar co-localization with the mitochondrial marker Mito-Tracker Red (Figure S6).…”

Section: Discussionmentioning

confidence: 95%

Cell Cycle Regulated Phosphorylation of the Telomere-Associated Protein TIN2

Yang

Counter

2013

PLoS ONE

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The protein TIN2 is a member of telomere-binding protein complex that serves to cap and protect mammalian chromosome ends. As a number of proteins in this complex are phosphorylated in a cell cycle-dependent manner, we investigated whether TIN2 is modified by phosphorylation as well. We performed phospho-proteomic analysis of human TIN2, and identified two phosphorylated residues, serines 295 and 330. We demonstrated that both these sites were phosphorylated during mitosis in human cells, as detected by Phos-tag reagent and phosphorylation-specific antibodies. Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase RSK2. Specifically, phosphorylation of TIN2 at both these residues was increased upon expression of RSK2 and reduced by an inhibitor of the RSK family of kinases. Moreover, RSK2 phosphorylated TIN2 in vitro. The identification of these specifically timed post-translational events during the cell cycle suggests a potential mitotic regulation of TIN2 by phosphorylation.

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TIN2 Stability Is Regulated by the E3 Ligase Siah2

Cited by 25 publications

References 58 publications

Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO

Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO

Regulators and Effectors of Siah Ubiquitin Ligases

Cell Cycle Regulated Phosphorylation of the Telomere-Associated Protein TIN2

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