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

• Published in: Cell death and differentiation 2013-07, Vol.20 (7), p.941-952
• Main Authors: Lee, Y Y, Moujalled, D, Doerflinger, M, Gangoda, L, Weston, R, Rahimi, A, de Alboran, I, Herold, M, Bouillet, P, Xu, Q, Gao, X, Du, X-J, Puthalakath, H
• Format: Article
• Language: English
• Subjects: 631/337; 631/80/82/23; 631/80/86; Animals; Apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins - deficiency; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - physiology; Bcl-2-Like Protein 11; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cells, Cultured; CREB-Binding Protein - physiology; Cyclic AMP - physiology; Cyclic AMP-Dependent Protein Kinases - physiology; Life Sciences; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Animal; Myocytes, Cardiac - pathology; Myocytes, Cardiac - physiology; Original Paper; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Receptors, Adrenergic, beta - physiology; Salivary alpha-Amylases - physiology; Signal Transduction - physiology; Stem Cells; Thymocytes - pathology; Thymocytes - physiology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.29

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.