The histone acetyltransferases CBP/p300 are degraded in NIH 3T3 cells by activation of Ras signalling pathway.
The CBP [CREB (cAMP-response-element-binding protein)-binding protein]/p300 acetyltransferases function as transcriptional co-activators and play critical roles in cell differentiation and proliferation. Accumulating evidence shows that alterations of the CBP/p300 protein levels are linked to human tumours. In the present study, we show that the levels of the CBP/p300 co-activators are decreased dramatically by continuous PDGF (platelet-derived growth factor) and Ras signalling pathway activation in NIH 3T3 fibroblasts. This effect occurs by reducing the expression levels of the CBP/p300 genes. In addition, CBP and p300 are degraded by the 26 S proteasome pathway leading to an overall decrease in the levels of the CBP/p300 proteins. Furthermore, we provide evidence that Mdm2 (murine double minute 2), in the presence of active H-Ras or N-Ras, induces CBP/p300 degradation in NIH 3T3 cells. These findings support a novel mechanism for modulating other signalling transduction pathways that require these common co-activators.
Sánchez-Molina
Sara
S
Instituto de Biología Molecular de Barcelona, CID, Consejo Superior de Investigaciones Científicas, Parc Cientific de Barcelona, Josep Samitier 1-5, 08028 Barcelona, Spain.
Oliva
José Luis
JL
García-Vargas
Susana
S
Valls
Ester
E
Rojas
José M
JM
Martínez-Balbás
Marian A
MA
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014633:Valine / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D010982:Platelet-Derived Growth Factor; D046988:Proteasome Endopeptidase Complex; D051736:Proto-Oncogene Proteins c-mdm2; D014157:Transcription Factors; D025801:Ubiquitin; D014633:Valine; D050880:p300-CBP Transcription Factors; D018631:ras Proteins; D000099224:p300-CBP-Associated Factor