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Status |
Public on Jul 01, 2016 |
Title |
Tunable regulation of CREB DNA binding activity couples genotoxic stress response and metabolism |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
In this study we show that, in embryonic fibroblasts from mice on a high fat diet and treated with Forskolin, ionizing radiation exposure or both, phosphorylation of CREB-binding protein (CREB) by ATM (ataxia-telangiectasia-mutated) and casein kinases 1 and 2 (CK1 and CK2) on a cluster of five phosphorylation sites (the ATM/CK cluster) within the unstructured kinase-inducible domain (KID) provides an additional level of regulation through dynamic modulation of CREB DNA binding activity. Stoichiometric phosphorylation of the ATM/CK cluster in response to DNA damage inhibited cAMP-induced CREB target gene expression, CREB DNA binding activity, and CREB-CRTC2-DNA ternary complex formation proportional to the number of phosphate residues modified. Substoichiometric phosphorylation of the ATM/CK cluster promoted cAMP/Ca2+-regulated transcriptional coactivators (CRTCs) recruitment and CREB activation via an ATM-independent, PKA-dependent pathway. Mice expressing a non-phosphorylatable CREBS111A allele exhibited phenotypes consistent with CREB deregulation, including fasting hyperglycemia, susceptibility to diet-induced obesity, and reduced expression of gluconeogenic genes.
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Overall design |
Two genotypes: CREB+/+ (wild type) and CREBS111A (non-phosphorylatable CREB KID S111A mutant allele) each control treated, exposed to forskolin, ionizing radiation or both in triplicate and in two batches toataling 48 arrays
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Contributor(s) |
Tibbetts RS, Kim S, Bushel PR |
Citation(s) |
27431323 |
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Submission date |
Jun 30, 2016 |
Last update date |
Feb 02, 2018 |
Contact name |
Pierre Robert Bushel |
E-mail(s) |
bushel@niehs.nih.gov
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Phone |
919-316-4564
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Organization name |
NIEHS
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Department |
Biostatistics and Computational Biology Branch
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Lab |
Bioinformatics
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Street address |
P.O. Box 12233
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City |
RTP |
State/province |
NC |
ZIP/Postal code |
27709 |
Country |
USA |
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Platforms (1) |
GPL10787 |
Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Probe Name version) |
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Samples (48)
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Relations |
BioProject |
PRJNA327300 |