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

Abstract

Catecholamines regulate the b-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 b-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. Cell Death and Differentiation (2013) 20, 941-952; doi:10.1038/cdd.2013 published online 12 April 2013 Cyclic adenosine monophosphate (cAMP) is a second messenger that is highly conserved throughout evolution. In metazoans, its primary role is to act as an intracellular carrier of metabolic information, regulating hormonal responses, 1 in triggering apoptotic cell death and in regulating ontogeny.2,3

BIM Is the Primary Mediator of MYC-Induced Apoptosis in Multiple Solid Tissues

“…Conversely, MYC dependent suppression of BCLXL and BCL2 sensitizes cells to γ-irradiation-induced apoptosis (Eischen et al, 2001, Maclean et al, 2003). The recent identification of BIM as a transcriptional target of MYC suggests that this BH3-only protein may directly mediate MYC’s pro-apoptotic signal (Campone et al, 2011, Lee et al, 2013). MYC induces BIM accumulation in Burkitt’s Lymphoma and MYC point mutants that fail to induce BIM also fail to induce apoptosis.…”

Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice

“…This is consistent with our previous finding that activation of PKA by b-AR agonists in fetal thymic organ cultures caused Bim induction and BIM-mediated apoptosis. 12 In the present study, loss of Bim had only limited impact on the induction of apoptosis in several non-hematopoietic tissues, including the Prkar1a deletion induces cachexia in mice L Gangoda et al heart, liver and kidneys. This indicates that other proapoptotic proteins, either on their own or in combination with Bim, might mediate this cell death.…”

“…33 In contrast, another report identified Prkar1a as a weak tumour promoter, 9 and our previous work revealed that increased PKA activity can elicit apoptosis, consistent with the notion that PRKAR1a may promote tumorigenesis. 11,12,34 We therefore hypothesized that Prkar1a loss or haploinsufficiency on its own would not be sufficient to promote tumour development. Tumorigenesis does not result from a single oncogenic mutation but is driven by a series of oncogenic lesions, each conferring some growth advantage.…”

“…Findings from our laboratory and others revealed that increased PKA activity caused transcriptional induction as well as posttranslational stabilization of the proapoptotic BH3-only protein BIM. [11][12][13] Moreover, PKA activation has been shown to promote differentiation and block proliferation in certain cell lines. [14][15][16][17] Increased PKA activity has also been reported to cause cardiomyocyte apoptosis, thereby leading to cardiomyopathy.…”

A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress

“…Indeed, increased PKA activity has been reported to promote apoptosis by causing transcriptional induction and post-translational stabilization of BIM. 29,34 In line with this, genetic deletion of Prkar1a leads to early embryonic lethality in mice, 35,36 and its inducible loss in diverse adult tissues is reported to trigger PKA activation and apoptosis because of the upregulation of proapoptotic BCL-2 family members. 15 Paradoxically, PKA is also reported to promote cell survival and its hyperactivation causes hereditary endocrine neoplasias.…”