The histone acetyltransferases CBP/p300 are degraded in NIH 3T3 cells by activation of Ras signalling pathway

• Published in: Biochemical journal 2006-09, Vol.398 (2), p.215-224
• Main Authors: Sánchez-Molina, Sara, Oliva, José Luis, García-Vargas, Susana, Valls, Ester, Rojas, José M, Martínez-Balbás, Marian A
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Enzyme Activation - drug effects; Gene Expression; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Mice; NIH 3T3 Cells; p300-CBP Transcription Factors; Platelet-Derived Growth Factor - pharmacology; Proteasome Endopeptidase Complex - metabolism; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Ubiquitin - metabolism; Valine - genetics; Valine - metabolism
• ISSN: 0264-6021; 1470-8728; 1470-8728
• DOI: 10.1042/BJ20060052

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.