SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia

Cheng, Jinke; Kang, Xunlei; Zhang, Sui; Yeh, Edward T.H.

doi:10.1016/j.cell.2007.08.045

Cited by 566 publications

(589 citation statements)

References 42 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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“…Recent reports have shown that a retrovirus insertional mutation within the mouse SENP1 gene caused downregulation of SENP1 expression and embryonic lethality at E12.5-E14.5. 40,41 Although mice with genetic deficiency in SENP1 (SENP1-KO) in our system were prenatal lethal (these findings will be described elsewhere), we were able to isolate mouse embryonic fibroblast cells (MEFs) from wildtype or SENP1-KO embryos at E13. SENP1 expression in MEFs was determined by western blot with anti-SENP1 antibody and results confirmed a defect of SENP1 in SENP1-KO MEF (Figure 7a).…”

Section: Resultsmentioning

confidence: 99%

SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

Luo

et al. 2008

Cell Death Differ

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We have previously shown that tumor necrosis factor (TNF)-induced desumoylation and subsequent cytoplasmic translocation of HIPK1 are critical for ASK1-JNK activation. However, the mechanism by which TNF induces desumoylation of HIPK1 is unclear. Here, we show that SENP1, a SUMO-specific protease, specifically deconjugates SUMO from HIPK1 in vitro and in vivo. In resting endothelial cells (ECs), SENP1 is localized in the cytoplasm where it is complexed with an antioxidant protein thioredoxin. TNF induces the release of SENP1 from thioredoxin as well as nuclear translocation of SENP1. TNF-induced SENP1 nuclear translocation is specifically blocked by antioxidants such as N-acetyl-cysteine, suggesting that TNF-induced translocation of SENP1 is ROS dependent. TNF-induced nuclear import of SENP1 kinetically correlates with HIPK1 desumoylation and cytoplasmic translocation. Furthermore, the wild-type form of SENP1 enhances, whereas the catalyticinactive mutant form or siRNA of SENP1 blocks, TNF-induced desumoylation and cytoplasmic translocation of HIPK1 as well as TNF-induced ASK1-JNK activation. More importantly, these critical functions of SENP1 in TNF signaling were further confirmed in mouse embryonic fibroblast cells derived from SENP1-knockout mice. We conclude that SENP1 mediates TNF-induced desumoylation and translocation of HIPK1, leading to an enhanced ASK1-dependent apoptosis. The small ubiquitin-like modifier (SUMO) can be covalently attached to a large number of proteins through the formation of isopeptide bonds with specific lysine residues of target proteins. 1,2 A large number of sumoylated proteins, including RanGAP1, PML, homeodomain-interacting protein kinases (HIPKs), IkB, p53, c-Jun, Sp3, Elk-1, p300 histone acetyltransferase, histone deacetylase (HDAC), and many nuclear receptors, have been identified. 1-3 Sumoylation is a dynamic process that is mediated by activating, conjugating, and ligating enzymes and that is readily reversed by a family of SUMO-specific proteases. 4 Several members of SUMOspecific proteases have been reported in the mammalian system. 5-10 SENP1 is a protease that appears to deconjugate a large number of sumoylated proteins. 5 Different members of these SUMO-specific proteases appear to localize in different cellular compartments where they regulate protein function by modifying the protein stability, cellular localization, and protein-protein interactions. 5,6,[8][9][10][11][12] However, it is not known how these SUMO-specific proteases are regulated.HIPK1 is one of three closely related serine/threonine protein kinases that are primarily localized in the nucleus where it is sumoylated. 13,14 The HIPKs were originally identified as nuclear protein kinases that function as co-repressors for various homeodomain-containing transcription factors. 15 Recently, HIPKs have been shown to interact with other proteins involved in apoptosis and signal transduction in a cellular localization-dependent manner. In nucleus, HIPK2 phosphorylates p53 on Ser 46, resulting in the activatio...

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“…PC3 luc cells were cultured in RPMI1640 in 10 % FCS, penicillin and streptomycin at 37 ° C and 5 % CO 2 . MEF cells from SENP1 homozygous null ( SENP1 − / − ) and WT ( SENP1 + / + ) mice 36 , which was provided by Dr J. K. Cheng in SJTU-SM, were cultured in DMEM with 10 % FBS. SENP1 + / + and SENP1 − / − MEFs were generated and maintained according to the protocol of Cheng et al .…”

Section: E N T I -V E C T O R L E N T I -V E C T O R Kdamentioning

confidence: 99%

“…SENP1 + / + and SENP1 − / − MEFs were generated and maintained according to the protocol of Cheng et al . 36 Cell transfection was performed using Lipofectamine 2000 ( Invitrogen ).…”

Section: E N T I -V E C T O R L E N T I -V E C T O R Kdamentioning

confidence: 99%

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

et al. 2012

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The membrane association of the tumour suppressor phosphatase and tensin homologue (PTEN) is required to oppose the phosphatidylinositol-3-kinase / AKT pathway by dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3). How cytosolic PTEN interacts with its main substrate, PIP3, localized at the inner face of plasma membrane remains unclear. Here we show that PTEN is covalently modifi ed by SUMO1 at both K 266 and K 254 sites in the C2 domain of PTEN. SUMO1 modifi cation at K 266 located in the CBR3 loop, which has a central role in PTEN membrane association, mainly facilitates cooperative binding of PTEN to the plasma membrane by electrostatic interactions. This results in the downregulation of the phosphatidylinositol-3 kinase / AKT pathway and consequently, suppression of anchorageindependent cell proliferation and tumour growth in vivo . Our data demonstrate a molecular mechanism whereby SUMO1 modifi cation is required for PTEN tumour suppressor function by controlling PTEN membrane association and regulation of the phosphatidylinositol-3 kinase / AKT pathway.

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SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia

Cited by 566 publications

References 42 publications

Turn me on: regulating HIF transcriptional activity

Turn me on: regulating HIF transcriptional activity

SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

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