Soutenance de thèse de Mme Malgorzata BOROWIAK du Laboratoire de Biologie Moléculaire de la Cellule de Lyon sous la direction de Mme Madeleine DUC DODON.
HTLV-1 (Human T-cell Leukemia Virus, type 1) infects 15-25 millions people worldwide and is a causative agent of adult T-cell leukemia (ATL). Induction of extended lifespan and increased proliferation of the infected cells, necessary to establish and promote leukemogenesis, occurs via a multistep process involving deregulation of cell signaling pathways, inactivation of tumor suppressors and perturbation of mitotic checkpoints.
The aim of this thesis was to better understand the deregulation of menin tumor suppressor function upon HTLV-1 infection and its implications in the leukemogenic process. Previous studies attributed the menin tumor suppressor properties mainly to its interaction with JunD cellular partner, as binding to menin converts this AP-1 factor into a growth suppressor, whereas it otherwise acts as a growth promoter. I demonstrated that HBZ viral protein abrogates the tumor suppressor function of menin, resulting in the activation of JunD transcriptional activity leading to the up-regulation of the human telomerase reverse transcriptase (hTERT). I showed that HBZ, JunD and menin can coexist in the same protein complex and that HBZ and menin exert opposite effects on JunD transcriptional activity. Moreover menin inhibits the JunD-mediated activation of the hTERT proximal promoter and HBZ is able to counteract this effect. Finally, I proposed that HBZ, by recruiting p300 histone acetyltransferase, reverses the histone deacetylation conducted by menin-recruited HDACs and therefore up-regulates the hTERT target promoter.
– Altogether, my work led to the identification of the molecular mechanism leading to the functional impairment of menin tumor suppressor, which results in deregulation of AP-1 signaling in HTLV-1 infected cells. Finally this work gave new insights into the understanding of the transcriptional up-regulation of telomerase reverse transcriptase (hTERT) upon HTLV-1 infection, being a key event during the development of Adult T-cell leukemia.
Salle des Thèses - Site Monod - ENS Lyon