title: CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)-mediated apoptosis.
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.
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, Australia.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Moujalled
authors.forename: M
authors.initials: M
authors.lastname: Doerflinger
authors.forename: L
authors.initials: L
authors.lastname: Gangoda
authors.forename: R
authors.initials: R
authors.lastname: Weston
authors.forename: A
authors.initials: A
authors.lastname: Rahimi
authors.forename: I
authors.initials: I
authors.lastname: de Alboran
authors.forename: M
authors.initials: M
authors.lastname: Herold
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: X-J
authors.initials: XJ
authors.lastname: Du
authors.forename: H
authors.initials: H
authors.lastname: Puthalakath
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D050882:CREB-Binding Protein / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D055291:Salivary alpha-Amylases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D060168:Thymocytes / Q000473:pathology* / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; C524799:Amy1 protein, mouse; D055291:Salivary alpha-Amylases