title: Cyclic AMP-induced p53 destabilization is independent of EPAC in pre-B acute lymphoblastic leukemia cells in vitro.
abstract: BACKGROUND
  Activation of the tumor suppressor protein p53 facilitates the cellular response to genotoxic stress. Thus, releasing the wild-type p53 from indirect suppression would be crucial to successful killing of cancer cells by DNA-damaging therapeutic agents.
  
  
  OBJECTIVE
  The aim of this study was to investigate the inhibitory role of cyclic adenosine monophosphate (cAMP) levels on p53 protein in acute lymphoblastic leukemia (ALL) cells. More importantly, we were interested to show through which receptor cAMP acts to promote p53 degradation.
  
  
  METHODS
  In cell cultures, we investigated the effects of forskolin/3-isobutyl-1-methylxanthine (IBMX) on stimulated p53 of ALL cell lines. Western blotting analysis was performed to detect the expression of p53, phospho-p53, acetylated-p53, phospho-cAMP response element-binding protein (CREB), and Mdm2 proteins. Flow cytometry was applied to analyze apoptosis. The gene expression of p53 and its target genes was examined by real-time polymerase chain reaction.
  
  
  RESULTS
  We show that elevation of cAMP levels in ALL cells exposed to DNA damage attenuates p53 accumulation. Inhibition of proteosome function with MG-132 reversed the inhibitory effect of cAMP on p53. However, targeting the p53-Mdm2 interaction did not rescue accumulated p53 from the destabilizing signal of cAMP. The specific agonist of the cAMP receptor exchange protein activated by cAMP had no effect on p53 expression in doxorubicin-treated NALM-6 cells, whereas PKA activators decreased p53 accumulation.
  
  
  CONCLUSIONS
  Our studies demonstrate that cAMP-PKA pathway regulates the sensitivity toward DNA-damaging agents via inhibition of a p53-dependent pathway in B-cell precursor ALL (BCP-ALL) cells.
authors: Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran. majid.safa@yahoo.com
authors: Majid
authors: M
authors: Safa
authors: Ahmad
authors: A
authors: Kazemi
authors: Farhad
authors: F
authors: Zaker
authors: Farnaz
authors: F
authors: Razmkhah