The transcriptional co-activator PCAF regulates cdk2 activity.
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.
Mateo
Francesca
F
Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Spain.
Vidal-Laliena
Miriam
M
Canela
Núria
N
Zecchin
Annalisa
A
Martínez-Balbás
Marian
M
Agell
Neus
N
Giacca
Mauro
M
Pujol
María Jesús
MJ
Bachs
Oriol
O
D000107:Acetylation; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D019925:Cyclin A; D051357:Cyclin-Dependent Kinase 2; D015534:Trans-Activators; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor