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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]

PMID: 23579242

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Project description:The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (A?42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The A?42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for A?42 mediated neurodegeneration is yet to be fully understood.We have utilized Gal4/UAS system to develop a transgenic fruit fly model for A?42 mediated neurodegeneration. Targeted misexpression of human A?42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of A?42 mediated neurodegeneration. Targeted misexpression of CBP along with A?42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues A?42 mediated neurodegeneration by blocking cell death. Misexpression of A?42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with A?42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.We have identified CBP as a genetic modifier of A?42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.

Dataset Information

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

Publications

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

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