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PMID:19773423

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Citation

Mateo, F, Vidal-Laliena, M, Canela, N, Zecchin, A, Martínez-Balbás, M, Agell, N, Giacca, M, Pujol, MJ and Bachs, O (2009) The transcriptional co-activator PCAF regulates cdk2 activity. Nucleic Acids Res. 37:7072-84

Abstract

Cyclin dependent kinases (cdks) regulate cell cycle progression and transcription. We report here that the transcriptional co-activator PCAF directly interacts with cdk2. This interaction is mainly produced during S and G(2)/M phases of the cell cycle. As a consequence of this association, PCAF inhibits the activity of cyclin/cdk2 complexes. This effect is specific for cdk2 because PCAF does not inhibit either cyclin D3/cdk6 or cyclin B/cdk1 activities. The inhibition is neither competitive with ATP, nor with the substrate histone H1 suggesting that somehow PCAF disturbs cyclin/cdk2 complexes. We also demonstrate that overexpression of PCAF in the cells inhibits cdk2 activity and arrests cell cycle progression at S and G(2)/M. This blockade is dependent on cdk2 because it is rescued by the simultaneous overexpression of this kinase. Moreover, we also observed that PCAF acetylates cdk2 at lysine 33. As this lysine is essential for the interaction with ATP, acetylation of this residue inhibits cdk2 activity. Thus, we report here that PCAF inhibits cyclin/cdk2 activity by two different mechanisms: (i) by somehow affecting cyclin/cdk2 interaction and (ii) by acetylating K33 at the catalytic pocket of cdk2. These findings identify a previously unknown mechanism that regulates cdk2 activity.

Links

PubMed PMC2790897 Online version:10.1093/nar/gkp777

Keywords

Acetylation; Animals; Cell Cycle; Cell Line; Cyclin A/antagonists & inhibitors; Cyclin A/metabolism; Cyclin-Dependent Kinase 2/antagonists & inhibitors; Cyclin-Dependent Kinase 2/metabolism; Mice; Trans-Activators/antagonists & inhibitors; Trans-Activators/metabolism; p300-CBP Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CDK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9JHD1

F

Seeded From UniProt

complete

MOUSE:CDK2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KAT2B

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P97377

F

Seeded From UniProt

complete

MOUSE:KAT2B

involved_in

GO:0018393: internal peptidyl-lysine acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KAT2B

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KAT2B

enables

GO:0004861: cyclin-dependent protein serine/threonine kinase inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:KAT2B

enables

GO:0004468: lysine N-acetyltransferase activity, acting on acetyl phosphate as donor

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:KAT2B

involved_in

GO:0045736: negative regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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