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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
|
| 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 |
| Submission date |
Jun 30, 2016 |
| Last update date |
Feb 02, 2018 |
| Contact name |
Pierre Robert Bushel |
| E-mail(s) |
bushel@niehs.nih.gov
|
| Phone |
919-316-4564
|
| Organization name |
NIEHS
|
| Department |
Biostatistics and Computational Biology Branch
|
| Lab |
Bioinformatics
|
| Street address |
P.O. Box 12233
|
| 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 |
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