CBP: A Signal-Regulated Transcriptional Coactivator Controlled by Nuclear Calcium and CaM Kinase IV

Abstract

Recruitment of the coactivator, CREB binding protein (CBP), by signal-regulated transcription factors, such as CREB [adenosine 3', 5'-monophosphate (cAMP) response element binding protein], is critical for stimulation of gene expression. The mouse pituitary cell line AtT20 was used to show that the CBP recruitment step (CREB phosphorylation on serine-133) can be uncoupled from CREB/CBP-activated transcription. CBP was found to contain a signal-regulated transcriptional activation domain that is controlled by nuclear calcium and calcium/calmodulin-dependent (CaM) protein kinase IV and by cAMP. Cytoplasmic calcium signals that stimulate the Ras mitogen-activated protein kinase signaling cascade or expression of the activated form of Ras provided the CBP recruitment signal but did not increase CBP activity and failed to activate CREB- and CBP-mediated transcription. These results identify CBP as a signal-regulated transcriptional coactivator and define a regulatory role for nuclear calcium and cAMP in CBP-dependent gene expression.

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

“…Meanwhile, it became clear that membrane depolarisation-induced calcium influx regulates not only CREB phosphorylation at Ser119 and thus the recruitment of CBP [7,29], but also targets CBP directly. Consistent with previous studies in the mouse pituitary cell line AtT20 [27], in cortical neurons [38], in hippocampal neurons [39] and in HIT beta cells [24], the present study confirms that membrane depolarisation stimulates CBP transcriptional activity. It demonstrates furthermore that DLK through its kinase activity markedly inhibits CBP transcriptional activity both under basal conditions and after stimulation by membrane depolarisation.…”

“…It demonstrates furthermore that DLK through its kinase activity markedly inhibits CBP transcriptional activity both under basal conditions and after stimulation by membrane depolarisation. Several kinases have been shown to activate CBP/p300, including calcium/calmodulin-dependent kinase IV, MAPKKK1 and ERK1/2 [27,[39][40][41]. As shown in the present study, DLK is the first example of a kinase that inhibits CBP transcriptional activity.…”

“…CBP is a large modular protein, and its C-terminus is known to exhibit strong transcriptional activity and to exert regulatory functions [8,27]. To examine whether DLK may have an effect on CBP, a GAL4-CBP C-terminus (amino acids 1,678-2,441) fusion protein was used together with the GAL4-luciferase reporter gene (Fig.…”

“…In addition to the phosphorylation on Ser119, CREB transcriptional activity is regulated by membrane depolarisation-induced signalling pathways at additional steps of CREB-mediated transcriptional activation [7,27]. It was thought initially that the CREB coactivator CBP confers constitutive transcriptional activity to promoter-bound CREB.…”

The social environment and the epigenome

“…Interestingly, NGFI-A was previously shown to regulate transcription of the transcriptional coactivator and histone acetyl transferase CREB binding protein CBP by both repression and activation under different cellular challenges [Yu et al, 2004]. Signaling pathways that result in increased cAMP also activate CBP [Chawla et al, 1998]. NGFI-A and CBP are recruited to the GR exon 1 7 promoter in response to maternal care which explains the increased acetylation and demethylation observed in offspring of high LG-ABN [Weaver et al, 2007].…”