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Blood, 16 July 2009, Vol. 114, No. 3, pp. 608-618. Prepublished online as a Blood First Edition Paper on May 18, 2009; DOI 10.1182/blood-2009-02-204883. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-02-204883v1 114/3/608    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Naderi, E. H. Articles by Naderi, S. PubMed PubMed Citation Articles by Naderi, E. H. Articles by Naderi, S. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Activation of cAMP signaling inhibits DNA damage–induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation Elin Hallan Naderi1, Harry W. Findley2, Ellen Ruud3, Heidi Kiil Blomhoff1, and Soheil Naderi1 1 Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo/Universitetet i Oslo, Oslo, Norway; 2 Division of Hematology/Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; and 3 Department of Paediatrics, Rikshospitalet, Oslo University Hospital, Oslo, Norway In lymphocytes, the second messenger cyclic adenosine monophosphate (cAMP) plays a well-established antiproliferative role through inhibition of G1/S transition and S-phase progression. We have previously demonstrated that, during S-phase arrest, cAMP inhibits the action of S phase–specific cytotoxic compounds, leading to reduction in their apoptotic response. In this report, we provide evidence that cAMP can also inhibit the action of DNA-damaging agents independently of its effect on S phase. Elevation of cAMP in B-cell precursor acute lymphoblastic leukemia cells is shown to profoundly inhibit the apoptotic response to ionizing radiation, anthracyclins, alkylating agents, and platinum compounds. We further demonstrate that this effect depends on the ability of elevated cAMP levels to quench DNA damage–induced p53 accumulation by increasing the p53 turnover, resulting in attenuated Puma and Bax induction, mitochondrial outer membrane depolarization, caspase activation, and poly(ADP-ribose) polymerase cleavage. On the basis of our findings, we suggest that cAMP levels may influence p53 function in malignant cells that retain wild-type p53, potentially affecting p53 both as a tumor suppressor during cancer initiation and maintenance, and as an effector of the apoptotic response to DNA-damaging agents during anticancer treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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