| Abstract [eng] |
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric protein that consist of two proteins- HIF-1α and HIF-1β. HIF-1 activates the transcription of many genes that code for proteins that are involved in angiogenesis, glucose metabolism, cell proliferation/survival and invasion/metastasis. HIF-1α protein degradation is regulated by O2-dependent prolyl hydroxylation, whitch targets the protein for ubiquitylation by E3 ubiquitin-protein ligases. These ligases contain the von Hippel-Lindau tumour-suppressor protein (VHL), whitch binds specifically to hydroxylated HIF-1α and ubiqutinates it. Ubiquitylated HIF-1α is rapidly degraded by the proteosome. HIF-1α interacts with the molecular chaperone Hsp90. Hsp90 plays a pivotal role in mediating the proper folding and subsequent activation of its numerous “client” proteins. Hsp90 also cooperates with the proteosomal pathway to eliminate misfolded cellular proteins. The antibiotic geldanamycin (GA) binds to Hsp90 and modulates its chaperone function, thereby accelerating the degradative activity associated with Hsp90. However, whether Hsp90 modulates HIF-1α activity by stabilization of the protein or by another mechanism is not clear. We tested the hypothesis weather and how inactivation (i.e. with geldanamycin) of Hsp90 protein function influences HIF-1α protein expression levels. Our obtained results shows that Hsp90 is required to HIF-1α protein under normoxia as well as hypoxia and is also essential for hypoxic HIF-1α activation. In conclusion, inhibition of chaperone Hsp90 with antibiotic geldanamycin leads to reduced cellular HIF-1α protein levels. |
