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


ABSTRACT: Catecholamines regulate the ?-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 ?-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.

SUBMITTER: Lee YY 

PROVIDER: S-EPMC3679460 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Lee Y Y YY   Moujalled D D   Doerflinger M M   Gangoda L L   Weston R R   Rahimi A A   de Alboran I I   Herold M M   Bouillet P P   Xu Q Q   Gao X X   Du X-J XJ   Puthalakath H H  

Cell death and differentiation 20130412 7


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-on  ...[more]

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