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
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 ). "
ABSTRACT: Populations living at high altitudes (HA), particularly in the Peruvian Central Andes, are characterised by presenting subjects with erythrocytosis and others with excessive erythrocytosis (EE)(Hb>21 g dl−1). EE is associated with chronic mountain sickness (CMS), or lack of adaptation to HA. Testosterone is an erythropoietic hormone and it may play a role on EE at HA. The objective of the present review was to summarise findings on role of serum T levels on adaptation at HA and genes acting on this process. Men at HA without EE have higher androstenedione levels and low ratio androstenedione/testosterone than men with EE, suggesting low activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and this could be a mechanism of adaptation to HA. Higher conversion of dehydroepiandrosterone to testosterone in men with EE suggests nigher 17beta-HSD activity. Men with CMS at Peruvian Central Andes have two genes SENP1, and ANP32D with higher transcriptional response to hypoxia relative to those without. SUMO-specific protease 1 (SENP1) is an erythropoiesis regulator, which is essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1α) under hypoxia. SENP1 reverses the hormone-augmented SUMOylation of androgen receptor (AR) increasing the transcription activity of AR.In conclusion, increased androgen activity is related with CMS.
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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. "
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.
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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). "
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.