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Les protéines ING2 et ING3 : identification de nouvelles fonctions et implication en cancérologie

Abstract : ING2 and ING3 are tumor suppressor proteins belonging to the ING (INhibitor of Growth) family. Tumor suppressor roles have been extensively described since the discovery of its five different members. My thesis focused on the identification of new functions for ING2 and ING3 proteins. The first objective was to understand the role of ING2 protein in the mitochondrial compartment. We demonstrated that ING2 protein is imported into the internal mitochondrial fraction, and that the disulfide relay system was involved in this process. We identified an interaction between ING2 and TFAM in relation with mitochondrial DNA. Loss of ING2 expression alters the mitochondrial ultrastructure, and protects tumor cells from oxidative phosphorylation inhibition. We proposed a new « gatekeeper » tumor suppressive function for ING2, in connection with the metabolic adaptation of tumor cells. The second part of my work was dedicated to the description of ING2 expression status in lung cancer. We demonstrated the prognosis significance of ING2 expression in the different cell compartments. We then shown that loss of ING2 expression resulted in susceptibility to WEE1 inhibition. Our results suggest a transcriptional control of ING2 on the CHK1 protein, main activator of WEE1 kinase. We therefore establish for the first time a therapeutic vulnerability dependent on the expression of an ING protein in a tumor model. The last objective of my thesis was to explore the role of ING3 in the specific context of prostate cancer. Our results confers a new oncogenic role for ING3. Its origin is due to a complex transcriptional network depedent on ING3, involving genes that regulates the cell cycle and the response to androgens. We therefore propose to modify the initial name of the ING3 protein in favor of "INducer of Growth 3".
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Submitted on : Friday, May 13, 2022 - 10:20:14 AM
Last modification on : Monday, May 16, 2022 - 10:15:16 AM

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Charles Ricordel. Les protéines ING2 et ING3 : identification de nouvelles fonctions et implication en cancérologie. Médecine humaine et pathologie. Université Rennes 1, 2022. Français. ⟨NNT : 2022REN1B002⟩. ⟨tel-03667155⟩

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