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Theses

Régulateurs traductionnels de l'expression génique de la différenciation et du stress cellulaire

Abstract : In cell, gene expression can be modified depending on the cellular microenvironment. Regulation of gene expression occurs at different levels, ranging from the transcription of the DNA to the mRNA. Among the post- transcriptional regulation, the control of translation plays a crucial role. In particular, the translational regulation occurs in response to different stimuli such as cell differentiation or cell stress. In stress condition, the canonical cap-dependent translation is blocked, excepted some mRNAs that are translated by alternative mechanisms. One of these mechanisms involves the structural elements of the mRNAs, the IRES (Internal Ribosome Entry Sites). The IRES activation involves some factors called ITAFs (IRES trans-acting factors), which allow the internal recruitement of ribosomes to initiate translation. My thesis is to study the mechanisms of IRES-dependent translation regulation in response to different stimuli, and to identify ITAFs responsible for this regulation. In the first part of my project, we have shown that the translation controlled by the FGF1 mRNA IRES is activated. This activation depends on its own promoter during the early phase of murine myoblast differentiation. Through biomolecular interaction analysis technology by surface plasmon resonance coupled to mass spectrometry (BIA/MS), we identified two proteins, p54nrb/NONO and hnRNPM bound both to the IRES and the FGF1gene promoter. These two proteins are both ITAFs activators of IRES and activators of FGF1 promoter transcription, resulting in a coupling of transcription and translation responsible for the induction of the FGF1 expression during myoblast differentiation. In the second part of this thesis, we demonstrated the existence of an IRES within the VEGFD mRNA. This IRES is activated by heat shock in mammary murine carcinoma. BIA/MS technology has enabled us to identify nucleolin as ITAF responsible for this activation. SHAPE experiments revealed the presence of two alternative structures of VEGFD IRES. According to our results, the heat shock induced the relocation of nucleolin from the nucleus to the cytoplasm, suggesting its binding to the mRNA in the cytoplasm could stabilize the conformation of the mRNA VEGFD IRES and activate its translation. The third part of my thesis focused on translational regulation of lymphangiogenic and angiogenic genes into cardiomyocytes in hypoxic conditions. The data obtained by the semi-global approach Fluidigm indicate that only few genes are induced at the transcriptional level, while the majority of them, especially those which have the mRNA IRES, are activated at translational level in hypoxic cardiomyocytes. I have also shown that the mRNA IRES of factors (lymph)angiogenic VEGF and FGF are activated during early hypoxia. Through Technology BIA/MS, I identified a specific hypoxic ITAF of FGF1 IRES in cardiomyocytes: it is the vasohibin - 1 protein involved in angiogenesis and stress tolerance. So, my thesis has enabled to make progress in understanding the mechanisms of IRES-dependent translation regulation. In addition, I have demonstrated that in cardiomyocytes during hypoxia the gene expression is surprisingly regulated at translational level. My work led to the identification of several molecular actors responsible for the regulation of mRNA (lymph)angiogenic factors translation, which could play a key role in ischemic pathologies and in cancer, and provide new targets therapeutic.
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Fransky Hantelys. Régulateurs traductionnels de l'expression génique de la différenciation et du stress cellulaire. Physiologie [q-bio.TO]. Université Paul Sabatier - Toulouse III, 2017. Français. ⟨NNT : 2017TOU30355⟩. ⟨tel-02067123⟩

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