Editors' ChoiceTranscriptional Regulation

Inhibiting CBP is "Rsk"y Business

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Science's STKE  25 Sep 2001:
Vol. 2001, Issue 101, pp. tw343
DOI: 10.1126/stke.2001.101.tw343

The cyclic AMP-responsive binding protein (CREB)-binding protein (CBP) and ribosomal protein S6 kinase 2 (Rsk2) can respectively acetylate and phosphorylate the DNA-binding protein histone H3, leading to increased accessibility of chromatin loci for transcription. Transcriptional accessibility to DNA is a tightly controlled process; however, the mechanisms by which the concerted modifications on histone H3 occur are not well understood. Merienne et al. may have identified the mechanism by which acetylation and phosphorylation are controlled. In cells deprived of serum, overexpressed Rsk2 and CBP existed in a complex, which did not include the transcriptional activator CREB. The protein complexes were disrupted by treatment of cells with epidermal growth factor, phorbol myristate acetate, or UV light. Phoshphoinositide-dependent protein kinase 1 (PDK1)-dependent phosphorylation of Rsk2 at Ser227 also disrupted the binding of Rsk2 and CBP in cells, suggesting that the specific protein-protein disruption required phosphorylation of Rsk2. Isolated complexes of Rsk2-CBP from quiescent cells contained greatly reduced kinase and acetylase activities toward in vitro substrates as compared with uncomplexed Rsk2 and CBP. Additionally, cells overexpressing CBP--presumably binding to all the available Rsk2--had lower amounts of phosphorylated CREB, suggesting that Rsk2 and CBP inhibited each other's enzymatic activity when associated in complexes. Dissociation of Rsk2 from CBP correlated with concomitant increases in CREB phosphorylation, which is required for CBP to bind CREB and essential for CBP-dependent acetylation of histone H3. Uncomplexed Rsk2 can phosphorylate histone H3. Thus, the authors propose that the proteins responsible for modifying histone H3 and making the chromatin accessible inhibit each other's activity until the appropriate signal (phosphorylation) is transduced to Rsk2.

K. Merienne, S. Pannetier, A. Harel-Bellan, P. Sassone-Corsi, Mitogen-regulated Rsk2-CBP interaction controls their kinase and acetylase activities. Mol. Cell. Biol. 21, 7089-7096 (2001). [Abstract] [Full Text]

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