HBZ-induced functional deregulation of menin - new insights into the mechanism of telomerase activation during HTLV-1-mediated leukemogenesis
type: Distribution
access URL: https://theses.hal.science/tel-00860179
format: HTML
issued: 2026-05-09T19:31:47.477401
modified: 2026-05-09T19:31:47.458900

HBZ-induced functional deregulation of menin - new insights into the mechanism of telomerase activation during HTLV-1-mediated leukemogenesis
type: Dataset
contact point: Organization
  fn: CCSD
keyword: leukemogenesis
keyword: ap-1-signaling
keyword: suppresseur-de-tumeur
keyword: voie-ap-1
keyword: htlv-1
keyword: theses
keyword: menine
keyword: tumor-suppressors
keyword: infoeu-reposemanticsdoctoralthesis
keyword: htert
keyword: hbz
keyword: sdvbclife-sciences-q-biocellular-biology
keyword: telomerase
keyword: menin
keyword: leucemie
landing page: https://theses.hal.science/tel-00860179
description: Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disorder associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Reactivation of telomerase, a critical event in tumor progression observed in late phases of ATL development, has been shown to be caused by HBZ (HTLV-1 bZIP factor), a regulatory protein encoded by the negative strand of the HTLV-1 genome. The HBZ-mediated up-regulation of the telomerase catalytic subunit is dependent on JunD, which in the cellular context occurs in the complex with menin, the product of the MEN-1 tumor suppressor gene. Interaction with menin represses JunD-dependent transcription and converts JunD into a growth suppressor, whereas it acts as a growth promoter in the absence of menin. My results demonstrate that the viral protein HBZ abrogates tumor suppressor function of menin, resulting in the activation of JunD transcriptional activity and finally in the up-regulation of its target gene, 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 expression of the hTERT gene. Altogether, my work led to the identification of the molecular mechanism leading to the functional impairment of the menin tumor suppressor, which results in the deregulation of AP-1 signaling in HTLV-1 infected cells. Finally this work gave new insights into the mechanism of the transcriptional up-regulation of the hTERT gene upon HTLV-1 infection, being a key event during the development of Adult T-cell leukemia and a necessary step towards the progression into more aggressive courses.
identifier: NNT: 2013ENSL0828
issued: 2026-05-09T19:31:47.473904
language: en
modified: 2026-05-09T19:31:47.473909

test_moissonnage_selune
type: Agent