title: cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases.
abstract: Activation of cAMP signalling potently inhibits DNA damage-induced apoptosis in acute lymphoblastic leukemia cells by promoting the turnover of p53 protein. Recently, we showed that the cAMP-induced destabilization of p53 in DNA-damaged cells occurs as a result of enhanced interaction between p53 and HDM2. In this report, we present results showing that increased levels of cAMP in cells with DNA damage enhances the deacetylation of p53, an event that facilitates the interaction of p53 with HDM2, thus annulling the stabilizing effect of DNA damage on p53. The combined inhibition of the HDAC and SIRT1 deacetylases abolished the cAMP-mediated deacetylation of p53, implying that cAMP-mediated deacetylation of p53 is dependent on the activity of these two classes of histone deacetylases. Importantly, diminishing the activity of HDACs and SIRT1 was also found to reverse the inhibitory effect of cAMP on the DNA damage-induced p53 stabilization and apoptosis, suggesting the involvement of the p53 acetylation pathway in the anti-apoptotic effect of cAMP signalling.
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Martine Müller
authors.initials: MM
authors.lastname: Kloster
authors.forename: Elin Hallan
authors.initials: EH
authors.lastname: Naderi
authors.forename: Ingvild
authors.initials: I
authors.lastname: Haaland
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Heidi Kiil
authors.initials: HK
authors.lastname: Blomhoff
authors.forename: Soheil
authors.initials: S
authors.lastname: Naderi
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000242:Cyclic AMP; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D006655:Histone Deacetylases