Cyclin-dependent kinase 1-dependent phosphorylation of cAMP response element-binding protein decreases chromatin occupancy.

Abstract

The cyclic AMP response element-binding protein (CREB) initiates transcriptional responses to a wide variety of stimuli. CREB activation involves its phosphorylation on Ser-133, which promotes interaction between the CREB kinase-inducible domain (KID) and the KID-interacting domain of the transcriptional coactivator, CREB-binding protein (CBP). The KID also contains a highly conserved phosphorylation cluster, termed the ATM/CK cluster, which is processively phosphorylated in response to DNA damage by the coordinated actions of ataxia-telangiectasia-mutated (ATM) and casein kinases (CKs) 1 and 2. The ATM/CK cluster phosphorylation attenuates CBP binding and CREB transcriptional activity. Paradoxically, it was recently reported that DNA damage activates CREB through homeodomain-interacting protein kinase 2-dependent phosphorylation of Ser-271 near the CREB bZIP DNA binding domain. In this study we sought to further clarify DNA damage-dependent CREB phosphorylation as well as to explore the possibility that the ATM/CK cluster and Ser-271 synergistically or antagonistically modulate CREB activity. We show that, rather than being induced by DNA damage, Ser-270 and Ser-271 of CREB cophosphorylated in a CDK1-dependent manner during G2/M phase. Functionally, we show that phosphorylation of CREB on Ser-270/Ser-271 during mitosis correlated with reduced CREB chromatin occupancy. Furthermore, CDK1-dependent phosphorylation of CREB in vitro inhibited its DNA binding activity. The combined results suggest that CDK1-dependent phosphorylation of CREB on Ser-270/Ser-271 facilitates its dissociation from chromatin during mitosis by reducing its intrinsic DNA binding potential.

• Authors: Anthony T Trinh, Sang Hwa Kim, Hae-yoon Chang, Adam S Mastrocola, Randal S Tibbetts
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 33 Pg. 23765-75 (Aug 16 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23814058 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• Cyclic AMP Response Element-Binding Protein
• Phosphoserine
• DNA
• CDC2 Protein Kinase
• Nocodazole

Topics

• Amino Acid Sequence
• CDC2 Protein Kinase (metabolism)
• Chromatin (metabolism)
• Cyclic AMP Response Element-Binding Protein (chemistry, metabolism)
• DNA (metabolism)
• DNA Damage
• Electrophoretic Mobility Shift Assay
• HEK293 Cells
• HeLa Cells
• Humans
• Molecular Sequence Data
• Nocodazole (pharmacology)
• Phosphorylation (drug effects)
• Phosphoserine (metabolism)
• Protein Binding (drug effects)
• Spindle Apparatus (drug effects, metabolism)