The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways

Qi, Jianfei; Nakayama, Koh; Gaitonde, Supriya; Goydos, James S.; Krajewski, Stan; Eroshkin, Alexey; Bar–Sagi, Dafna; Bowtell, David D.L.; Ronai, Ze’ev A.

doi:10.1073/pnas.0804063105

Cited by 93 publications

(128 citation statements)

References 35 publications

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“…Pharmacological inhibition of Siah2 might be a promising approach to increase PHD abundance and attenuate the HIF response. Proof-of-principle has been provided by expression of small protein inhibitors of Siah which attenuated growth of xenografted tumors [67,70,71]. Increasing the complexity, FIH has also been claimed to be ubiquitinylated and degraded in a Siah1-dependent manner, providing evidence that besides regulation of HIF stability, Siah proteins might also play a role in fine-tuning the transcriptional activity of HIFs [72,73].…”

Section: Siah2mentioning

confidence: 99%

HIF Prolyl-4-hydroxylase Interacting Proteins: Consequences for Drug Targeting

Wenger¹,

Camenisch²,

Stiehl³

et al. 2009

CPD

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Protein stability of hypoxia-inducible factor (HIF) subunits is regulated by the oxygen-sensing prolyl-4-hydroxylase domain (PHD) enzymes. Under oxygen-limited conditions, HIF subunits are stabilized and form active HIF transcription factors that induce a large number of genes involved in adaptation to hypoxic conditions with physiological implications for erythropoiesis, angiogenesis, cardiovascular function and cellular metabolism. Oxygen-sensing is regulated by the co-substrate-dependent activity and hypoxia-inducible abundance of the PHD enzymes which trigger HIF stability even under low oxygen conditions. Because HIF itself is notoriously reluctant to the development of antagonists, an increase in PHD activity would offer an interesting alternative to the development of drugs that interfere specifically with the HIF signalling pathway. Interestingly, among the recently discovered PHD interacting proteins were not only novel downstream targets but also upstream regulators of PHDs. Their PHD isoform-specific interaction offers the possibility to target distinct PHD isoforms and their non-identical downstream signalling pathways. This review summarizes our current knowledge on PHD interacting proteins, including upstream regulators, chaperonins, scaffolding proteins, and novel downstream transcription factors.

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Section: Siah2mentioning

confidence: 99%

HIF Prolyl-4-hydroxylase Interacting Proteins: Consequences for Drug Targeting

Wenger¹,

Camenisch²,

Stiehl³

et al. 2009

CPD

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show abstract

“…In addition, inhibition of the expression of Siah had an anti-tumorigenic effect in mouse melanoma, SW1 cells, and breast cancer cells [33] . Inhibition of the binding of Siah with the substrates through PHYL also reduced tumor growth, angiogenesis, and metastatic spread by the inactivated hypoxic response pathway [34] . Furthermore, in vivo, a chemical inhibitor of Siah2, menadione, abolished the growth of xenograft tumors in nude mice [35] .…”

Section: Function Of Siah As a Tumor Sup-pressor Protein And Its Rolementioning

confidence: 99%

“…In Siah2 knockout mice, tumor onset was found to be delayed; in addition, the mice exhibited an abrogated response to hypoxic conditions. At cellular and tissue levels, the expression of Siah2 mutants under hypoxic conditions led to significantly lower protein levels of HIF-1, resulting in reduced hypoxia-induced gene expression [34] .…”

Section: Function Of Siah In Hypoxic Re-sponse and Its Role In Myocarmentioning

confidence: 99%

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

Baba¹,

Miyazaki²

2016

Journal of Biochemistry and Molecular Biology Research

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The seven in absentia homolog (Siah) family proteins are components of E3 ubiquitin ligase complexes that catalyze the ubiquitination of proteins. Siah proteins target their substrates for proteasomal degradation. Several studies have reported that Siah proteins are involved in tumorigenesis and angiogenesis, particularly through the Ras and HIF-1a signaling pathways in hypoxic response. Recent studies also have reported that Siah2 stabilization impairs the NF-E2-related factor 2 (Nrf2) signaling pathway, which is a master regulator of reactive oxygen species (ROS) metabolism. Hypoxia induces the phosphorylation of Nrf2 and then decreases the Keap1-mediated degradation of Nrf2 compared with that under normoxia. In addition, hypoxia-induced Siah2 provides a dominating Nrf2 degradation pathway over that of Keap1 under hypoxia. Given their critical roles in ROS metabolism, Siah proteins are attractive targets for effective therapy under particular conditions such as hypoxia and hypoglycemia.

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“…Inhibition of Siah reportedly attenuates breast, pancreatic, lung, prostate, and melanoma tumors (13-16). Mechanistically, Siah2 contributes to tumor development and metastasis via its control of diverse substrates, as shown in a melanoma model (14).A search for novel Siah2 interacting factors led to identification of the isopeptidase USP13 (17). This protease shares a 54.8% identity with its isoform USP5 (18,19).…”

mentioning

confidence: 99%

“…The role of Siah2 in tumor development has been extensively studied. Inhibition of Siah reportedly attenuates breast, pancreatic, lung, prostate, and melanoma tumors (13)(14)(15)(16). Mechanistically, Siah2 contributes to tumor development and metastasis via its control of diverse substrates, as shown in a melanoma model (14).…”

mentioning

confidence: 99%

USP13 Enzyme Regulates Siah2 Ligase Stability and Activity via Noncatalytic Ubiquitin-binding Domains

Scortegagna

Subtil

et al. 2011

Journal of Biological Chemistry

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The RING finger E3 ubiquitin ligase Siah2 is implicated in control of diverse cellular biological events, including MAPK signaling and hypoxia. Here we demonstrate that Siah2 is subject to regulation by the deubiquitinating enzyme USP13. Overexpression of USP13 increases Siah2 stability by attenuating its autodegradation. Consequently, the ability of Siah2 to target its substrates prolyl hydroxylase 3 and Spry2 (Sprouty2) for ubiquitin-mediated proteasomal degradation is attenuated. Conversely, inhibition of USP13 expression with corresponding shRNA decreases the stability of both Siah2 and its substrate Spry2. Thus, USP13 limits Siah2 autodegradation and its ubiquitin ligase activity against its target substrates. Strikingly, the effect of USP13 on Siah2 is not mediated by its isopeptidase activity: mutations in its ubiquitin-binding sequences positioned within the ubiquitin-specific processing protease and ubiquitin-binding domains, but not within putative catalytic sites, abolish USP13 binding to and effect on Siah2 autodegradation and targeted ubiquitination. Notably, USP13 expression is attenuated in melanoma cells maintained under hypoxia, thereby relieving Siah2 inhibition and increasing its activity under low oxygen levels. Significantly, on melanoma tissue microarray, high nuclear expression of USP13 coincided with high nuclear expression of Siah2. Overall, this study identifies a new layer of Siah2 regulation mediated by USP13 binding to ubiquitinated Siah2 protein with a concomitant inhibitory effect on its activity under normoxia.Siah proteins are RING finger E3 ubiquitin ligases implicated in the ubiquitination and proteasome-dependent degradation of substrate molecules, which also limit their own availability through self-ubiquitination and degradation (1-3). Siah was first identified in Drosophila melanogaster as seven in absentia (sina), which regulates formation of the R7 photoreceptor through control of tramtrack stability (4, 5). Three murine Siah genes (Siah1a, Siah1b, and Siah2) share significant homology with the two human (SIAH1 and SIAH2) orthologues (6, 7).Siah2 is an important regulator of pathways activated under stress and hypoxia. Among substrates reportedly regulated by Siah under these conditions are TRAF2, ␣-ketoglutarate dehydrogenase, Spry2 (Sprouty2), and two of the three prolyl hydroxylases (8 -10). Given the role of PHD proteins as oxygen sensors and regulators of HIF1␣, the master transcription factor responding to hypoxia, Siah is implicated in the control of hypoxia, particularly within the range of 2-6% oxygen at which PHD proteins retain sufficient activity (11,12). The role of Siah2 in tumor development has been extensively studied. Inhibition of Siah reportedly attenuates breast, pancreatic, lung, prostate, and melanoma tumors (13-16). Mechanistically, Siah2 contributes to tumor development and metastasis via its control of diverse substrates, as shown in a melanoma model (14).A search for novel Siah2 interacting factors led to identification of the isopeptidase USP13 ...

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The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways

Cited by 93 publications

References 35 publications

HIF Prolyl-4-hydroxylase Interacting Proteins: Consequences for Drug Targeting

HIF Prolyl-4-hydroxylase Interacting Proteins: Consequences for Drug Targeting

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

USP13 Enzyme Regulates Siah2 Ligase Stability and Activity via Noncatalytic Ubiquitin-binding Domains

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