cAMP Signalling in Modification of DNA Damage Responses in Lymphoid Cells : Implications for Development and Treatment of BCP-ALL
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AbstractDNA damage responses are important both in the development and treatment of cancers. The main focus of the present thesis has been to explore whether the level of the second messenger cAMP can affect the cell’s response to DNA damage with particular emphasis on the apoptotic response in lymphoid cells. By studying cells from B cell precursor acute lymphoblastic leukaemia (BCP-ALL), we could show that augmented cAMP signalling resulted in marked protection against DNA damage-induced apoptosis. cAMP conferred no protection to normal BCPs, indicating that the effect of cAMP on cell survival is a malignancy associated trait. Investigation into the mechanistic background for the attenuated apoptotic response revealed that cAMP acted at the level of p53 induction by counteracting the DNA damage-induced stabilization of the p53 protein. Furthermore, cAMP appears to augment the interaction between p53 and its major negative regulator HDM2, resulting in sustained p53 ubiquitination and proteasomal degradation despite the presence of DNA damage. Activation of p53 is an obligate feature of cellular transformation, and the subsequent induction of senescence or apoptosis is assumed central to the role of p53 as a major tumour suppressor. Based on our findings, we hypothesized that augmentation of cAMP signalling might be exploited in BCP-ALL to serve an anti-tumour-suppressive purpose. We found no evidence of constitutively elevated cAMP levels in BCP-ALL cells. However, co-culture experiments indicate that bone marrow stromal interactions might provide the leukaemic blasts with cAMP-elevating pro-survival signals. Furthermore, we found that inhibition of cAMP signalling tended to potentiate DNA damage-induced cell death in leukaemic cells. Thus we conclude that augmentation of cAMP signalling might be of relevance to understand the development of and modulate the treatment against BCP-ALL.
List of papers
|I. Naderi EH, Findley HW, Ruud E, Blomhoff HK, Naderi S. Activation of cAMP signaling inhibits DNA damage-induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation. Blood. 2009 Jul 16;114(3):608-18. The published version of this paper is available at: https://doi.org/10.1182/blood-2009-02-204883|
|II. Naderi EH, Naderi S, Jochemsen AG, Blomhoff HK. Activation of cAMP signalling interferes with stress-induced p53 accumulation in ALL-derived cells by promoting the interaction between p53 and HDM2. Submitted for publication.|
|III. Kloster MM, Hafte TT, Moltzau LR, Naderi EH, Dahle MK, Skalhegg BS, Gaudernack G, Levy FO, Naderi S, Blomhoff HK. EBV infection renders B cells resistant to growth inhibition via adenylyl cyclase. Cell Signal. 2008 Jun;20(6):1169-78. The published version of this paper is available at: https://doi.org/10.1016/j.cellsig.2008.02.007|
|IV. Naderi EH, Ugland HK, Diep PP, Josefsen D, Sandnes D, Myklebost O, Ruud E, Naderi S, Blomhoff HK. Selective inhibition of cell death in malignant versus normal B cell precursors: Implications for cAMP in development and treatment of BCP-ALL. Manuscript.|