Tunable regulation of CREB DNA binding activity couples genotoxic stress response and metabolism

Abstract

cAMP response element binding protein (CREB) is a key regulator of glucose metabolism and synaptic plasticity that is canonically regulated through recruitment of transcriptional coactivators. Here we show that phosphorylation of CREB on a conserved cluster of Ser residues (the ATM/CK cluster) by the DNA damage-activated protein kinase ataxia-telangiectasia-mutated (ATM) and casein kinase1 (CK1) and casein kinase2 (CK2) positively and negatively regulates CREB-mediated transcription in a signal dependent manner. In response to genotoxic stress, phosphorylation of the ATM/CK cluster inhibited CREB-mediated gene expression, DNA binding activity and chromatin occupancy proportional to the number of modified Ser residues. Paradoxically, substoichiometric, ATM-independent, phosphorylation of the ATM/CK cluster potentiated bursts in CREB-mediated transcription by promoting recruitment of the CREB coactivator, cAMP-regulated transcriptional coactivators (CRTC2). Livers from mice expressing a non-phosphorylatable CREB allele failed to attenuate gluconeogenic genes in response to DNA damage or fully activate the same genes in response to glucagon. We propose that phosphorylation-dependent regulation of DNA binding activity evolved as a tunable mechanism to control CREB transcriptional output and promote metabolic homeostasis in response to rapidly changing environmental conditions.

IL-1β suppression of VE-cadherin transcription underlies sepsis-induced inflammatory lung injury

“…We next determined whether CREB regulated VE-cadherin transcription and thereby promoted lung endothelial barrier function. CREB is known to bind preferentially the palindromic (TGACGTCA) or half-site (TGAC/G) cyclic AMP response elements (CREs) (18). The 2.5-kb mouse and human VE-cadherin promoter regions contain several of these conserved CREs for CREB binding (Supplemental Figure 2).…”

Glucose Availability Alters Gene and Protein Expression of Several Newly Classified and Putative Solute Carriers in Mice Cortex Cell Culture and D. melanogaster

“…Three promoter motifs, the TATA box, CCAAT box and the GC box were analyzed. The JASPER CORE 2018 vertebrate library was used to search for transcription factor motifs and several transcriptions factors known to be affected by macronutirent metabolism were analyzed; Atf4 (Averous et al, 2004;Dey et al, 2012), Cebpa (Pedersen et al, 2007), Cebpb (Ramji and Foka, 2002), Creb1 (Kim et al, 2016;Steven et al, 2017), E2f1 (Denechaud et al, 2017), FoxO1 (Kousteni, 2012), Mlx, Mlxip, and Mlxipl (Ma et al, 2006;Havula and Hietakangas, 2012).…”

ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses

“…It has since been demonstrated that in response to ROS, ATM phosphorylates downstream targets such as the Chk2 protein kinase and p53 transcription factor [29]. Similarly, CREB is also a direct target for ATM phosphorylation, which serves to regulate CREB-dependent transcriptional activity in response to DNA damage and cellular oxidative stress [30]. In 2010, Guo et al found that ATM is indeed activated in response to oxidative stress in an MRN-independent manner that is separate from its DSB activation [31].…”