Sumoylation increases HIF-1α stability and its transcriptional activity

Bae, Seong-Hui; Jeong, Joo‐Won; Park, Jeong Ae; Kim, Sehee; Bae, Moon‐Kyoung; Choi, Soo-Joon; Kim, Kyu‐Won

doi:10.1016/j.bbrc.2004.09.068

Cited by 200 publications

(165 citation statements)

References 26 publications

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“…41 SUMOylation of HIF-1a has also been described by several groups, however the reported outcomes of this modification are varied. For example, in a number of studies, SUMOylation of HIF-1a has been suggested to both increase HIF-1a stability and transcriptional activity, 57,58 but in others, it has been suggested to decrease activity and enhance VHLmediated ubiquitination 59,60 Transcriptional Cofactors…”

Section: Other Modifications Affecting Hif-driven Transcriptionmentioning

confidence: 99%

Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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Section: Other Modifications Affecting Hif-driven Transcriptionmentioning

confidence: 99%

Turn me on: regulating HIF transcriptional activity

2008

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“…3A. Autoradiograph from the incubations of (His) 6 -tagged hARD1 with [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]-AcCoA and HIF-1a 504-553 . The arrowed band corresponds to acetylated (His) 6 -tagged hARD1.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]-AcCoA (50 nCi) was incubated with enzyme (10 lg) and substrate (10 lg) and made up to a final volume of 10 ll with reaction buffer as described. The pH of the incubations was varied in one set of assays; subsequent self-acetylation studies were performed at pH 10.…”

Section: Analysis Of Acetyltransferase Activitymentioning

confidence: 99%

Purified recombinant hARD1 does not catalyse acetylation of Lys₅₃₂ of HIF‐1α fragments in vitro

et al. 2006

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In humans, many responses to hypoxia including angiogenesis and erythropoiesis are mediated by the a/b-heterodimeric transcription factor hypoxia inducible factor (HIF). The stability and/or activity of human HIF-1a are modulated by post-translational modifications including prolyl and asparaginyl hydroxylation, phosphorylation, and reportedly by acetylation of the side-chain of Lys 532 by ARD1 (arrest defective protein 1 homologue), an acetyltransferase. Using purified recombinant human ARD1 (hARD1) we did not observe ARD1-mediated N-acetylation of Lys 532 using fragments of HIF-1a. However, recombinant hARD1 from Escherichia coli was produced with partial N-terminal acetylation and was observed to undergo slow self-mediated N-terminal acetylation. The observations are consistent with the other data indicating that hARD1, at least alone, does not acetylate HIF-1a, and with reports on the N-terminal acetyltransferase activity of a recently reported heterodimeric complex comprising hARD1 and N-acetyltransferase protein.

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“…Originally, Bae et al [46] found that ectopic SUMO-1 expression in HEK 293T cells increases the stability of cotransfected HIF-1, thus enhancing the transcriptional activity of HIF-1 protein in which HIF-1 is sumoylated at lysines 391 and 477. CarbiaNagashima et al [48] reported that the RWD-containing sumoylation enhancer (RSUME) is induced by hypoxia and enhances overall SUMO-1, -2, and -3 conjugation.…”

Section: Sumoylation and Hif-1mentioning

confidence: 99%

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Jiao

et al. 2014

Sci. China Life Sci.

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Hypoxia-inducible factor-1 (HIF-1) is a key heterodimeric transcription factor for the cellular adaptive response to hypoxia, a common feature of the microenvironment in solid tumors. The transcriptional activity, protein stabilization, protein-protein interactions and cellular localization of HIF-1, an oxygen-sensitive subunit of HIF-1, are mainly modulated by various post-translational modifications. Recently, we reported that polycomb chromobox 4 (Cbx4) governs the transcriptional activity of HIF-1α by enhancing its sumoylation at K391 and K477, through which Cbx4 potentiates angiogenesis of hepatocellular carcinoma. This review summarizes the current knowledge of HIF-1 sumoylation and its roles in the pathogenesis of cancer.

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Sumoylation increases HIF-1α stability and its transcriptional activity

Cited by 200 publications

References 26 publications

Turn me on: regulating HIF transcriptional activity

Turn me on: regulating HIF transcriptional activity

Purified recombinant hARD1 does not catalyse acetylation of Lys₅₃₂ of HIF‐1α fragments in vitro

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

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Sumoylation increases HIF-1α stability and its transcriptional activity

Cited by 200 publications

References 26 publications

Turn me on: regulating HIF transcriptional activity

Turn me on: regulating HIF transcriptional activity

Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF‐1α fragments in vitro

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

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Purified recombinant hARD1 does not catalyse acetylation of Lys₅₃₂ of HIF‐1α fragments in vitro