P38α MAPK is required for contact inhibition

Proliferation of nontransformed cells is regulated by cell cell contacts, which are referred to as contact-inhibition. Despite its generally accepted importance for cell cycle control, knowledge about the intracellular signalling pathways involved in contact inhibition is scarce. In the present work we show that p38 alpha mitogen-activated protein kinase (MAPK) is involved in the growth-inhibitory signalling cascade of contact inhibition in fibroblasts. p38 alpha activity is increased in confluent cultures of human fibroblasts compared to proliferating cultures. Time course studies show a sustained activation of p38 alpha in response to cell-cell contacts in contrast to a transient activation after serum stimulation. The induction of contact inhibition by addition of glutaraldehyde-fixed cells is impaired by pharmacological inhibition of p38 as well as in p38 alpha-/- fibroblasts. Further evidence for a central role of p38a in contact inhibition comes from the observation that p38 alpha-/- fibroblasts show a higher saturation density compared to wild-type (wt) fibroblasts, which is reversed by reconstituted expression of p38 alpha. In agreement with a defect in contact inhibition, p27(Kip1) accumulation is impaired in p38 alpha-/- fibroblasts compared to wt fibroblasts. Hence, our work shows a new role for p38 alpha in contact inhibition and provides a mechanistic basis for the recently proposed tumour suppressive function of this MAPK pathway.