bcl-2 regulates hif-1α protein stabilization in hypoxic melanoma cells via the molecular chaperone hsp90稳定蛋白bcl - 2调节hif-1α黑色素瘤细胞在缺氧一半寿命通过分子伴侣.pdfVIP

Bcl-2 Regulates HIF-1a Protein Stabilization in Hypoxic Melanoma Cells via the Molecular Chaperone HSP90 1 1,2 1 2 1 Daniela Trisciuoglio , Chiara Gabellini , Marianna Desideri , Elio Ziparo , Gabriella Zupi , Donatella Del Bufalo1* 1 Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy, 2 Department of Histology and Medical Embryology, Sapienza University, Rome, Italy Abstract Background: Hypoxia-Inducible Factor 1 (HIF-1) is a transcription factor that is a critical mediator of the cellular response to hypoxia. Enhanced levels of HIF-1a, the oxygen-regulated subunit of HIF-1, is often associated with increased tumour angiogenesis, metastasis, therapeutic resistance and poor prognosis. It is in this context that we previously demonstrated that under hypoxia, bcl-2 protein promotes HIF-1/Vascular Endothelial Growth Factor (VEGF)-mediated tumour angiogenesis. Methodology/Principal Findings: By using human melanoma cell lines and their stable or transient derivative bcl-2 overexpressing cells, the current study identified HIF-1a protein stabilization as a key regulator for the induction of HIF-1 by bcl-2 under hypoxia. We also demonstrated that bcl-2-induced accumulation of HIF-1a protein during hypoxia was not due to an increased gene transcription or protein synthesis. In fact, it was related to a modulation of HIF-1a protein expression at a post-translational level, indeed its degradation rate was faster in the control lines than in bcl-2 transfectants. The bcl-2- induced HIF-1a stabilization in response to low oxygen tension conditions was achieved through the impairment of ubiquitin-depende