Expression and functional validation of new p38α transcriptional targets in tumorigenesis.

p38α MAPK (mitogen-activated protein kinase) plays an important tumour suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumour suppressor mechanisms co-ordinated by p38α have been reported to occur at the post-translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analysed whole-genome expression profiles of Ras-transformed wild-type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumours, and functional validation has identified several of them as probable mediators of the tumour suppressor effect of p38α on Ras-induced transformation. Interestingly, approx. 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF (epidermal growth factor) receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumour suppression.