Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2.
The p300-CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) involved in the reversible acetylation of various transcriptional regulators, including the tumour suppressor p53. It is implicated in many cellular processes, such as transcription, differentiation, proliferation and apoptosis. We observed that knockdown of PCAF expression in HeLa or U2OS cell lines induces stabilization of the oncoprotein Hdm2, a RING finger E3 ligase primarily known for its role in controlling p53 stability. To investigate the molecular basis of this effect, we examined whether PCAF is involved in Hdm2 ubiquitination. Here, we show that PCAF, in addition to its acetyltransferase activity, possesses an intrinsic ubiquitination activity that is critical for controlling Hdm2 expression levels, and thus p53 functions. Our data highlight a regulatory crosstalk between PCAF and Hdm2 activities, which is likely to have a central role in the subtle control of p53 activity after DNA damage.
Linares
Laëtitia K
LK
Centre de Recherches de Biochimie Macromoléculaire, CNRS-UMII UMR5237, Montpellier, France.
Kiernan
Rosemary
R
Triboulet
Robinson
R
Chable-Bessia
Christine
C
Latreille
Daniel
D
Cuvier
Olivier
O
Lacroix
Matthieu
M
Le Cam
Laurent
L
Coux
Olivier
O
Benkirane
Monsef
M
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D001665:Binding Sites / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016372:RNA, Antisense / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D009353:Zinostatin / Q000494:pharmacology; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051548:Histone Acetyltransferases; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D016372:RNA, Antisense; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D009353:Zinostatin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493956:CDKN1A protein, human; C498702:PMAIP1 protein, human; C497206:MDM2 protein, human