CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)-mediated apoptosis

Y. Y. Lee, D. Moujalled, Marcel Doerflinger, Lahiru Gangoda, R. Weston, Awat Rahimi, I. De Alboran, Marco Herold, Philippe Bouillet, Q. Xu, X. Gao, X. J. Du, H. Puthalakath

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

Abstract

Catecholamines regulate the β-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases.

Original languageEnglish
Pages (from-to)941-952
Number of pages12
JournalCell Death and Differentiation
Volume20
Issue number7
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

Keywords

  • β-adrenoceptor
  • Apoptosis
  • Bim
  • Cyclic AMP
  • Protein kinase A

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