Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1α signaling under hypoxia

Shi, Hengliang; Bao, Zheng; Wu, Yuxuan; Tang, Yuan; Wang, Lei; Gao, Yong; Gong, Hui; Du, Jin; Yu, Rutong

doi:10.3892/or.2014.3695

Cited by 24 publications

(28 citation statements)

References 31 publications

(39 reference statements)

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“…The seven-in-absentia homologue (Siah) RING-type E3 ubiquitin ligases Siah1 and Siah2 regulate the stability of the HIF hydroxylases PHD1, PHD3 and FIH through polyubiquitination [32][33][34][35][36][37]. Of note, the human genome encodes for two Siah homologues (Siah1 and Siah2), whereas in mice three functional Siah genes have been identified (Siah1a, Siah1b, Siah2) [38,39].…”

Section: Functional Interplay Between the Hif Pathway And E3 Ligases mentioning

confidence: 99%

“…The substrate-binding domain (SBD) of human Siah2 7 shows a high affinity for PHD3, while the SBD of human Siah1 only weakly interacts with it [35]. But in human glioma cells also Siah1 has been linked to the regulation of PHD3 protein levels and in the human breast cancer cell line MCF7 both Siah1 and 2 are involved in PHD3 protein degradation [36,37]. Silencing of either one of the two Siah E3 ligases resulted in increased PHD3 protein levels [36].…”

Section: Functional Interplay Between the Hif Pathway And E3 Ligases mentioning

confidence: 99%

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The functional interplay between the HIF pathway and the ubiquitin system – more than a one-way road

Günter

Ruiz-Serrano

Wenger

et al. 2017

Experimental Cell Research

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The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue functions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalyzed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage. The best-studied function is the targeting of proteins for proteasomal degradation. The activity of E3 ligases is antagonized by proteins called deubiquitinases (or deubiquitinating enzymes), which negatively regulate ubiquitin chains. This is performed in most cases by the catalytic removal of these chains from the targeted protein. The HIF pathway is regulated in an oxygen-dependent manner by oxygen-sensing hydroxylases. Covalent modification of HIFα subunits leads to the recruitment of an E3 ligase complex via the von Hippel-Lindau (VHL) protein and the subsequent polyubiquitination and proteasomal degradation of HIFα subunits, demonstrating the regulation of the HIF pathway by the ubiquitin system. This unidirectional effect of an E3 ligase on the HIF pathway is the best-studied example for the interplay between these two important cellular processes. However, additional regulatory mechanisms of the HIF pathway through the ubiquitin system are emerging and, more recently, also the reciprocal regulation of the ubiquitin system through components of the HIF pathway. Understanding these mechanisms and their relevance for the activity of each other is of major importance for the comprehensive elucidation of the oxygen-dependent regulation of cellular processes. This review describes the current knowledge of the functional bidirectional interplay between the HIF pathway and the ubiquitin system on the protein level.

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Section: Functional Interplay Between the Hif Pathway And E3 Ligases mentioning

confidence: 99%

Section: Functional Interplay Between the Hif Pathway And E3 Ligases mentioning

confidence: 99%

The functional interplay between the HIF pathway and the ubiquitin system – more than a one-way road

Günter

Ruiz-Serrano

Wenger

et al. 2017

Experimental Cell Research

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“…The construction of stable cell lines was carried out as we previously described . For stable silencing of SH3GL2, the U251 cells were infected by control and SH3GL2 #1‐3 viruses, respectively.…”

Section: Methodsmentioning

confidence: 99%

Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling

Zhu

Zhang

Wang

et al. 2017

J Cellular Molecular Medi

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SH3GL2 (Src homology 3 (SH3) domain GRB2‐like 2) is mainly expressed in the central nervous system and regarded as a tumour suppressor in human glioma. However, the molecular mechanism of the SH3GL2 protein involved in malignant behaviours of human glioma has not been elucidated. In this study, we tried to investigate the role of SH3GL2 in glioma cell migration and invasion and explore its underlined molecular mechanism. Firstly, we discovered that the protein level of SH3GL2 was widely decreased in the human glioma patients, especially in high‐grade glioma tissues. Then, we determined the role of SH3GL2 in migration and invasion of glioma cells upon SH3GL2 knocking down and overexpressing. It was showed that knocking down of SH3GL2 promoted the migration and invasion of glioma cells, whereas overexpression of SH3GL2 inhibited them. Further study on molecular mechanism disclosed that silencing of SH3GL2 obviously activated the STAT3 (signal transducer and activator of transcription 3) signalling thereby promoting the expression and secretion of MMP2. On the contrary, overexpression of SH3GL2 had opposite effect. Taken together, the above results suggest that SH3GL2 suppresses migration and invasion behaviours of glioma cells through negatively regulating STAT3/MMP2 signalling and that loss of SH3GL2 may intensify the STAT3/MMP2 signalling thereby contributing to the migration and invasion of glioma cells.

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“…A large number of studies already confirmed that hypoxia could induce autophagy [135][136][137]. More intriguing is that hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a heterodimeric transcription factor that mediates adaptive responses to hypoxia and can also be induced under anoxic condition [138][139][140]. In view of the above fact that hypoxia can activate HIF-1 alpha, and can also promote autophagy, the problem whether HIF-1 alpha could regulate autophagy under anoxic condition has been lingering in the minds of scholars.…”

Section: The Focus Of Autophagy Regulation: Hif-1 Alphamentioning

confidence: 98%

The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target

Zhang

Guo

Zhao

et al. 2015

Biomedicine & Pharmacotherapy

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Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1α signaling under hypoxia

Cited by 24 publications

References 31 publications

The functional interplay between the HIF pathway and the ubiquitin system – more than a one-way road

The functional interplay between the HIF pathway and the ubiquitin system – more than a one-way road

Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling

The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target

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