Article

Activation of cAMP signaling interferes with stress-induced p53 accumulation in ALL-derived cells by promoting the interaction between p53 and HDM2.

Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Neoplasia (New York, N.Y.) (Impact Factor: 5.48). 07/2011; 13(7):653-63.
Source: PubMed

ABSTRACT The tumor suppressor p53 provides an important barrier to the initiation and maintenance of cancers. As a consequence, p53 function must be inactivated for a tumor to develop. This is achieved by mutation in approximately 50% of cases and probably by functional inactivation in the remaining cases. We have previously shown that the second messenger cAMP can inhibit DNA damage-induced wild-type p53 accumulation in acute lymphoblastic leukemia cells, leading to a profound reduction of their apoptotic response. In the present article, we provide a mechanistic insight into the regulation of p53 levels by cAMP. We show that increased levels of cAMP augment the binding of p53 to its negative regulator HDM2, overriding the DNA damage-induced dissociation of p53 from HDM2. This results in maintained levels of p53 ubiquitination and proteasomal degradation, which in turn counteracts the DNA damage-induced stabilization of the p53 protein. The apoptosis inhibitory effect of cAMP is further shown to depend on this effect on p53 levels. These findings potentially implicate deregulation of cAMP signaling as a candidate mechanism used by transformed cells to quench the p53 response while retaining wild-type p53.

0 0
 · 
0 Bookmarks
 · 
101 Views
  • [show abstract] [hide abstract]
    ABSTRACT: Improvements in technology and resources are helping to advance our understanding of cancer-initiating events as well as factors involved with tumor progression, adaptation, and evasion of therapy. Tumors are well known to contain diverse cell populations and intratumor heterogeneity affords neoplasms with a diverse set of biologic characteristics that can be used to evolve and adapt. Intratumor heterogeneity has emerged as a major hindrance to improving cancer patient care. Polygenic cancer drug resistance necessitates reconsidering drug designs to include polypharmacology in pursuit of novel combinatorial agents having multitarget activity to overcome the diverse and compensatory signaling pathways in which cancer cells use to survive and evade therapy. Advances will require integration of different biomarkers such as genomics and imaging to provide for more adequate elucidation of the spatially varying location, type, and extent of diverse intratumor signaling molecules to provide for a rationale-based personalized cancer medicine strategy.
    Neoplasia (New York, N.Y.) 12/2012; 14(12):1278-89. · 5.48 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: B cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most commonly occurring paediatric cancer. Despite its relatively good prognosis, there is a steady search for strategies to improve treatment effects, and to prevent the undesired side effects on normal cells. In the present paper we demonstrate a differential effect of cAMP signalling between normal BCPs and BCP-ALL blasts, pointing to a potential therapeutic window allowing for manipulation of cAMP signalling in treatment of BCP-ALL. By studying primary cells collected from paediatric BCP-ALL patients and healthy controls, we found that cAMP profoundly decreased basal and DNA damage-induced p53 levels and cell death in malignant cells, whereas normal BCP counterparts rather displayed slightly augmented cell death when exposed to cAMP-increasing agents. We did not find evidence for a selection process involving generation of increased basal cAMP levels in BCP-ALL cells, but demonstrate that paracrine signalling involving PGE(2)-induced cAMP generation has the potential to suppress p53 activation and cell death induction. The selective inhibitory effect of cAMP signalling on DNA damage-induced cell death in BCP-ALL cells appears to be an acquired trait associated with malignant transformation, potentially allowing the use of inhibitors of this pathway for directed killing of the malignant blasts.
    Blood 01/2013; · 9.06 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The future of personalized oncological therapy will likely rely on evidence-based medicine to integrate all of the available evidence to delineate the most efficacious treatment option for the patient. To undertake evidence-based medicine through use of targeted therapy regimens, identification of the specific underlying causative mutation(s) driving growth and progression of a patient's tumor is imperative. Although molecular subtyping is important for planning and treatment, intraclonal genetic diversity has been recently highlighted as having significant implications for biopsy-based prognosis. Overall, delineation of the clonal architecture of a patient's cancer and how this will impact on the selection of the most efficacious therapy remain a topic of intense interest.
    Neoplasia (New York, N.Y.) 12/2013; 15(12):1410-1420. · 5.48 Impact Factor

Full-text

View
0 Downloads
Available from