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Rôle des protéines de choc thermique dans la régulation du facteur de transcription HIF

Abstract : Both HIF1α and HIF2α proteins are highly involved in the development of pathologies, such as cancers, which are prime public health issues. These proteins are primarily controlled at the protein level by ubiquitin-dependant degradation, and regulate numerous cellular processes which are likely to favor the development of these diseases. A recent issue in therapeutic research is to identify partners that might regulate the expression and the activity of the HIFα proteins, with the aim to elaborate targeted therapies. Heat shock proteins (HSPs) form a family of proteins whose main function is to regulate protein homeostasis in cells, which they achieve through interaction with the ubiquitin-proteasome pathway. HSP27 and HSP90 are able to specifically control the stability of certain client proteins involved in those pathologies. In the present work, we sought to determine whether these HSPs could regulate the expression of the HIF2α protein. Our results suggest that HSP27 may induce ubiquitin and proteasome-dependant degradation of HIF2α, which is quite intriguing given the well-known role of HSP27 in tumor promotion. This needs to be confirmed and the underlying biological significance of such a regulation remains to be defined. Our results also may confirm that HIF2α is an HSP90 client protein. Moreover, we show for the first time that inhibition of HSP90 by 17-DMAG decreases the HIF2α-dependant VEGF production. Recent studies emphasize HIF2α as a major promoter of tumor progression, and suggest that HIF2α may constitute an attractive global target in several cancer types. Therefore, the ability of HSP90 inhibitors to disrupt newly described HIF2α functions, such as cancer stem cell maintenance, should be evaluated.
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Submitted on : Tuesday, June 5, 2012 - 5:57:23 PM
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  • HAL Id : tel-00704624, version 1

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Sébastien Maurel. Rôle des protéines de choc thermique dans la régulation du facteur de transcription HIF. Sciences agricoles. Université de Bourgogne, 2011. Français. ⟨NNT : 2011DIJOS073⟩. ⟨tel-00704624⟩

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