Caractérisation des événements moléculaires et cellulaires de l’apoptose induite par rbf1, l'homologue de drosophile du gène suppresseur de tumeur rb

The inactivation of the retinoblastoma susceptibility gene (rb) is a preliminary step in the development of many cancers. Consistent with its role of tumor suppressor, pRb inhibits cell proliferation. The role of pRb in apoptosis control is more complex and the molecular mechanisms underlying these functions are poorly described.rbf1 is the rb Drosophila homologue. During my PhD, I characterized the apoptosis pathway induced by Rbf1 in a proliferative tissue. I showed that Rbf1 cooperates with the dE2F2 transcription factor and with the dREAM complex to stimulate the transcription of how gene coding for a RNA binding protein able to induce the degradation of diap1 caspase inhibitor transcripts. Furthermore, Rbf1/dE2F2 proteins repress the transcription of buffy (anti-apoptotic gene of Bcl-2 family) and thus trigger a mitochondrial death pathway dependent of debcl (pro-apoptotic gene of Bcl-2 family). A mitochondrial fragmentation dependent of the Drp1 pro-fission protein promotes the accumulation of reactive oxygen species, which in turn causes JNK pathway activation, leading ultimately to apoptosis. This work clarifies the mechanism of action of Bcl-2 proteins in drosophila. It brings new data about Rbf1 pro-apoptotic function and should provide a better understanding of pRb tumor suppressor activity. Finally, I showed that Rbf1-induced apoptosis leads to compensatory proliferation and defined for the first time specific actors of the JNK pathway involved in this proliferation.