Article

Induction of SENP1 in Endothelial Cells Contributes to Hypoxia-driven VEGF Expression and Angiogenesis

Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2010; 285(47):36682-8. DOI: 10.1074/jbc.M110.164236
Source: PubMed

ABSTRACT

SENP1 (SUMO-specific protease 1) has been shown to be essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1α) under hypoxia conditions. However, it is unknown how SENP1 activation and hypoxia signaling are coordinated in the cellular response to hypoxia. Here, we report the essential role of SENP1 in endothelial cells as a positive regulator of hypoxia-driven VEGF production and angiogenesis. SENP1 expression is increased in endothelial cells following exposure to hypoxia. Silencing of HIF-1α blocks SENP1 expression in cell response to hypoxia. Mutation of the hypoxia response element (HRE) on the Senp1 promoter abolishes its transactivation in response to hypoxia. Moreover, silencing of SENP1 expression decreases VEGF production and abrogates the angiogenic functions of endothelial cell. We also find that the elongated endothelial cells in embryonic brain section and vascular endothelial cells in embryonic renal glomeruli in Senp1(-/-) mice are markedly reduced than those in wild-type. Thus, these results show that hypoxia implies a positive feedback loop mediated by SENP1. This feedback loop is important in VEGF production, which is essential for angiogenesis in endothelial cells.

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    • "Hypoxia implies a positive feedback loop mediated by SENP1. This feedback loop is important in VEGF production, which is essential for angiogenesis in endothelial cells (Xu et al., 2010 ). In SENP1(À/À) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporterInterestingly, SENP-1 mediated GATA1 deSUMOylation is critical for definitive erythropoiesis (Yu et al., 2010 ). "
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    • "A key regulator of HIF-1α SUMOylation under hypoxia in general, including in cancer cells, is SENP1 62,63. A positive feedback loop exists between SENP1 and HIF-1α, as HIF-1α directly regulates transcription of the SENP1 gene 65. Transgenic overexpression of SENP1 in the mouse prostate gland increases HIF-1α, VEGF, and angiogenesis 66. "
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    • "Regulation of SUMO proteases can also occur through other mechanisms including transcription (Lee et al. 2011a), phosphorylation (Baldwin et al. 2009), proteasomal degradation (Itahana et al. 2006; Kuo et al. 2008; Yan et al. 2010), various stimuli like oxidative stress, oxygen deprivation/hypoxia (Huang et al. 2009; Xu et al. 2008; Cheng et al. 2007; Xu et al. 2010), and upon heat shock (Pinto et al. 2012). In yeast, mitotic phosphorylation of Ulp2 appeared to inhibit its isopeptidase functions with concomitant stabilization of sumoylated substrates (Baldwin et al. 2009; Bachant et al. 2002). "
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