title: Transcriptional down-regulation of Bcl-2 by vinorelbine: identification of a novel binding site of p53 on Bcl-2 promoter.
abstract: The Bcl-2 family contains a panel of proteins which are conserved regulators of apoptosis in mammalian cells, like the anti-apoptotic protein Bcl-2. According to its significant role in altering susceptibility to apoptosis, the deciphering of the mechanism of Bcl-2 expression modulation may be crucial for identifying therapeutics strategies for cancer. Treatment with microtubule-targeting agents, including taxanes and Vinca alkaloids, generally leads to a decrease in Bcl-2 intracellular amounts. Whereas the interest for these chemotherapeutics is accompanied by advances in the fundamental understanding of their anticancer properties, the molecular mechanism underlying changes in Bcl2 expression remains poorly understood. We report here that p53 contributes to vinorelbine-induced Bcl-2 down-regulation. Indeed, the decrease in Bcl-2 protein levels observed during vinorelbine-induced apoptosis was correlated to the decrease in mRNA levels, as a result of the inhibition of Bcl-2 transcription and promoter activity. In this context, we evaluated p53 contribution in the Bcl-2 transcriptional down-regulation. We identified, by chromatin immunoprecipitation, a novel p53 binding site in the Bcl-2 promoter, within a region upstream P(1) promoter. We showed that vinorelbine treatment increased this interaction in A549 cells. This work strengthens the links between p53 and Bcl-2 at a transcriptional level, upon microtubule-targeting agent treatment. Our study also provides answers that will be useful to assess microtubule-targeting agents' mechanism of action and that may help to better understand and increase their effectiveness.
authors: INSERM UMR 911, Centre de Recherche en Oncologie biologique et en Oncopharmacologie, Aix-Marseille Université, Faculté de Pharmacie, 27 Boulevard Jean Moulin, Marseille Cedex 05, France. veronique.rey@univmed.fr
authors: Véronique
authors: V
authors: Bourgarel-Rey
authors: Amandine
authors: A
authors: Savry
authors: Guoqiang
authors: G
authors: Hua
authors: Manon
authors: M
authors: Carré
authors: Céline
authors: C
authors: Bressin
authors: Christine
authors: C
authors: Chacon
authors: Jean
authors: J
authors: Imbert
authors: Diane
authors: D
authors: Braguer
authors: Yves
authors: Y
authors: Barra
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D014747:Vinblastine; D000077235:Vinorelbine