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CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)-mediated apoptosis
Y Y Lee1, D Moujalled, M Doerflinger
1Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, Australia.
Cell Death and Differentiation
|April 13, 2013
Summary
The β-adrenoceptor/cyclic AMP/protein kinase A (cAMP/PKA) pathway triggers apoptosis by inducing the Bim protein. Loss of Bim abrogates this catecholamine-mediated cell death, revealing a novel therapeutic target.
Area of Science:
- Molecular biology
- Cellular signaling
- Neuroendocrinology
Background:
- The β-adrenoceptor/cyclic AMP/protein kinase A (cAMP/PKA) pathway regulates critical cellular functions.
- Deregulation of this pathway is linked to diseases like neurodegeneration and cardiomyopathy.
- The precise molecular mechanisms driving pathway-induced apoptosis remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which the β-adrenoceptor/cAMP/PKA pathway induces apoptosis.
- To identify key molecular players involved in catecholamine-mediated cell death.
- To explore potential therapeutic targets for diseases linked to neuroendocrine system dysfunction.
Main Methods:
- Investigated the role of the β-adrenoceptor/cAMP/PKA pathway in apoptosis.
- Utilized knockout models to assess the function of Bim in catecholamine-induced cell death.
- Examined the transcriptional regulation of Bim, focusing on CBP and c-Myc interactions.
Main Results:
- Demonstrated that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis via transcriptional induction of the pro-apoptotic protein Bim.
- Showed that catecholamine-mediated apoptosis in tissues like the thymus and heart is dependent on Bim.
- Identified CBP and c-Myc as key drivers of Bim induction through altered histone modifications at the Bim promoter.
Conclusions:
- The β-adrenoceptor/cAMP/PKA pathway induces apoptosis through Bim.
- Bim is essential for catecholamine-mediated cell death in specific tissues.
- CBP and c-Myc-mediated transcriptional regulation of Bim offers insights into neuroendocrine disease pathophysiology.
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