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


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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    • "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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    ABSTRACT: The expression of 15-lipoxygenase-1 (15-LOX-1) is downregulated in colon cancer and other major cancers, and 15-LOX-1 reexpression in cancer cells suppresses colonic tumorigenesis. Various lines of evidence indicate that 15-LOX-1 expression suppresses premetastatic stages of colonic tumorigenesis; nevertheless, the role of 15-LOX-1 loss of expression in cancer epithelial cells in metastases continues to be debated. Hypoxia, a common feature of the cancer microenvironment, promotes prometastatic mechanisms such as the upregulation of hypoxia-inducible factor (HIF)-1α, a transcriptional master regulator that enhances cancer cell metastatic potential, angiogenesis, and tumor cell invasion and migration. We have, therefore, tested whether restoring 15-LOX-1 in colon cancer cells affects cancer cells' hypoxia response that promotes metastasis. We found that 15-LOX-1 reexpression in HCT116, HT29LMM, and LoVo colon cancer cells inhibited survival, vascular endothelial growth factor (VEGF) expression, angiogenesis, cancer cell migration and invasion, and HIF-1α protein expression and stability under hypoxia. These findings demonstrate that 15-LOX-1 expression loss in cancer cells promotes metastasis and that therapeutically targeting ubiquitous 15-LOX-1 loss in cancer cells has the potential to suppress metastasis.
    Cancer Medicine 06/2014; 3(3). DOI:10.1002/cam4.222 · 2.50 Impact Factor
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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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    ABSTRACT: Posttranslational modification of proteins by the small ubiquitin-like modifier (SUMO) is a potent regulator of various cellular events. Hundreds of substrates have been identified, many of them involved in vital processes like transcriptional regulation, signal transduction, protein degradation, cell cycle regulation, DNA repair, chromatin organization, and nuclear transport. In recent years, protein sumoylation increasingly attracted attention, as it could be linked to heart failure, cancer, and neurodegeneration. However, underlying mechanisms involving how modification by SUMO contributes to disease development are still scarce thus necessitating further research. This review aims to critically discuss currently available concepts of the SUMO pathway, thereby highlighting regulation in the healthy versus diseased organism, focusing on neurologic aspects. Better understanding of differential regulation in health and disease may finally allow to uncover pathogenic mechanisms and contribute to the development of disease-specific therapies.
    Neuromolecular medicine 08/2013; 15(4). DOI:10.1007/s12017-013-8258-6 · 3.68 Impact Factor
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    • "Work by Berta et al., 2007 reported that when HIF1α is conjugated to SUMO, its transcriptional activity is decreased and that this is not mediated by a change in the protein's half-life [60]. Most importantly, HIF1α also regulates SENP1 as a transcriptional factor, thus contributing to formation of a positive feedback loop which is important in VEGF production, essential for angiogenesis in endothelial cells [61]. "
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    ABSTRACT: SUMO (small ubiquitin-related modifier) conjugation is a reversible three-step process of protein post-translational modifications mediating protein-protein interactions, subcellular compartmentalization and regulation of transcriptional events. Among divergent transcription factors regulated by SUMOylation and deSUMOylation, the androgen receptor (AR) is of exceptional significance, given its established role in prostate carcinogenesis. The enzymes of the SUMO pathway can have diverse effects on AR transcriptional activity, either via direct modification of the AR or through modification of AR co-regulators. Accumulating in vitro and in vivo evidence implicates the SUMO pathway in AR-dependent signaling. Prostate cancer cell proliferation and hypoxia-induced angiogenesis are also regulated by the SUMO pathway, through an AR-independent mechanism. Thus, an important role has been revealed for members of the SUMO pathway in prostate cancer (PCa) development and progression, offering new therapeutic targets.
    12/2012; 2(2):240-55. DOI:10.3390/biom2020240
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