Ubiquitination is absolutely required for the degradation of hypoxia-inducible factor - 1 alpha protein in hypoxic conditions

Wang, Ronghai; Zhang, Ping; Guan, Hongzai; Shi, Guangjun

doi:10.1016/j.bbrc.2016.01.005

Cited by 10 publications

(6 citation statements)

References 31 publications

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“…The functional annotation of miRNAs target genes in database shows correlations of biological processes, molecular functions and pathways with hallmark responses to hypobaric-hypoxic stress and other HA stress conditions (7,(52)(53)(54). Hence this supports the comprehensive biomolecular structure of the database.…”

Section: Hahmirdb Statisticssupporting

confidence: 67%

“…'Cell cycle regulation' is an important cellular mechanism induced by the hypoxic stress that governs the cell fate from cell proliferation to apoptosis and is widely reported and studied biological process during hypoxic environments (52). The 'cellular response to oxygen level' is governed by Prolylhydroxylases (PHD) oxygen sensors of cells that controls the activation of HIF during low oxygen condition which further regulates hypoxic stress adaptative responses (7,(52)(53)(54). Similarly 'transcription factor binding', 'protein kinase binding', 'cell adhesion molecule binding', etc.…”

Section: Hahmirdb Statisticsmentioning

confidence: 99%

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HAHmiR.DB: A Server Platform For High Altitude Human miRNA-Gene Coregulatory Networks And Associated Regulatory-Circuits

Khurana

Gupta

Sugadev

et al. 2020

Preprint

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Rapid ascent to High Altitude (HA) can cause severe damage to body organs and may lead to many fatal disorders. During induction to HA, human body undergoes various physiological, biochemical, hematological and molecular changes to adapt to the extreme environmental conditions. Many literature references hint that gene-expression-regulation and regulatory molecules like microRNAs (miRNAs) and Transcription Factors (TFs) control adaptive responses during HA-stress. These biomolecules are known to interact in a complex combinatorial manner to fine-tune the gene expression and help in controlling the molecular responses during this stress and ultimately help in acclimatization. HAHmiR.DB (High-Altitude Human miRNA Database) is a unique, comprehensive, curated collection of miRNAs that have been experimentally validated to be associated with HA-stress; their level of expression in different altitudes, fold change, experiment duration, biomarker association, disease and drug association, tissue-specific expression level, Gene Ontology (GO) and Kyoto Encyclopaedia of Gene and Genomes (KEGG) pathway associations. As a server platform it also uniquely constructs and analyses interactive miRNA-TF-Gene coregulatory networks and extracts regulatory-circuits/Feed Forward Loops (FFLs) using in-house scripts. These regulatory circuits help to offer mechanistic insights in complex regulatory mechanisms during HA stress. The server can also build these regulatory networks between two and more miRNAs of the database and also identify the regulatory-circuits from this network. Hence HAHmiR.DB is the first-of its-kind database in HA research which a reliable platform to explore, compare, analyse and retrieve miRNAs associated with HA stress, their coregulatory networks and FFL regulatory circuits. HAHmiR.DB is freely accessible at http://www.hahmirdb.in

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Section: Hahmirdb Statisticssupporting

confidence: 67%

Section: Hahmirdb Statisticsmentioning

confidence: 99%

HAHmiR.DB: A Server Platform For High Altitude Human miRNA-Gene Coregulatory Networks And Associated Regulatory-Circuits

Khurana

Gupta

Sugadev

et al. 2020

Preprint

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“…A large body of research has demonstrated that HIF1␣ is regulated via a decrease in ubiquitination and subsequent increase in protein stability after a hypoxic stress (12). Our results suggested an additional component in regard to HIF1␣ expression, specifically the regulation of HIF1␣ translation/ polyadenylation by CPEB2 isoforms.…”

Section: Cpeb2a and Cpeb2b Regulate Twist1 And Hif1␣ At The Translatimentioning

confidence: 51%

Splice variants of cytosolic polyadenylation element–binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis

DeLigio¹,

Lin²,

Chalfant

et al. 2017

Journal of Biological Chemistry

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The translational regulator cytosolic polyadenylation element-binding protein 2 (CPEB2) has two isoforms, CPEB2A and CPEB2B, derived by alternative splicing of RNA into a mature form that either includes or excludes exon 4. Previously, we reported that this splicing event is highly dysregulated in aggressive forms of breast cancers, which overexpress CPEB2B. The loss of CPEB2A with a concomitant increase in CPEB2B was also required for breast cancer cells to resist cell death because of detachment (anoikis resistance) and metastasize To examine the mechanism by which CPEB2 isoforms mediate opposing effects on cancer-related phenotypes, we used next generation sequencing of triple negative breast cancer cells in which the isoforms were specifically down-regulated. Down-regulation of the CPEB2B isoform inhibited pathways driving the epithelial-to-mesenchymal transition and hypoxic response, whereas down-regulation of the CPEB2A isoform did not have this effect. Examining key nodes of these pathways showed that CPEB2B induced the expression of regulatory DNA-factors ( HIF1α and TWIST1). Specifically, CPEB2B functioned as a translational activator of TWIST1 and HIF1α. Functional studies showed that specific down-regulation of either HIF1α or TWIST1 inhibited the ability of CPEB2B to induce the acquisition of anoikis resistance and drive metastasis. Overall, this study demonstrates that CPEB2 alternative splicing is a major regulator of key cellular pathways linked to anoikis resistance and metastasis.

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“…2B). Of note, a recent investigation of VHL-independent degradation of HIF-1 in hypoxia indicates that ubiquitination is absolutely required for this regulation, highlighting further the importance of the interplay of the HIF pathway and the ubiquitin system [48]. To our knowledge, the regulation of E3 ligases by HIF through protein:protein interaction has not been reported so far.…”

Section: Hif Transcription Factor Subunits and E3 Ligasesmentioning

confidence: 98%

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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Ubiquitination is absolutely required for the degradation of hypoxia-inducible factor - 1 alpha protein in hypoxic conditions

Cited by 10 publications

References 31 publications

HAHmiR.DB: A Server Platform For High Altitude Human miRNA-Gene Coregulatory Networks And Associated Regulatory-Circuits

HAHmiR.DB: A Server Platform For High Altitude Human miRNA-Gene Coregulatory Networks And Associated Regulatory-Circuits

Splice variants of cytosolic polyadenylation element–binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis

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

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