p38alpha 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 p38alpha mitogen-activated protein kinase (MAPK) is involved in the growth-inhibitory signalling cascade of contact inhibition in fibroblasts. p38alpha activity is increased in confluent cultures of human fibroblasts compared to proliferating cultures. Time course studies show a sustained activation of p38alpha 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 p38alpha-/- fibroblasts. Further evidence for a central role of p38alpha in contact inhibition comes from the observation that p38alpha-/- fibroblasts show a higher saturation density compared to wild-type (wt) fibroblasts, which is reversed by reconstituted expression of p38alpha. In agreement with a defect in contact inhibition, p27(Kip1) accumulation is impaired in p38alpha-/- fibroblasts compared to wt fibroblasts. Hence, our work shows a new role for p38alpha in contact inhibition and provides a mechanistic basis for the recently proposed tumour suppressive function of this MAPK pathway.
Faust
Dagmar
D
Institute of Toxicology, Johannes Gutenberg-University, Obere Zahlbacherstr. 67, 55131 Mainz, Germany.
Dolado
Ignacio
I
Cuadrado
Ana
A
Oesch
Franz
F
Weiss
Carsten
C
Nebreda
Angel R
AR
Dietrich
Cornelia
C
D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003260:Contact Inhibition; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D009369:Neoplasms / Q000503:physiopathology; D015398:Signal Transduction
D048308:Mitogen-Activated Protein Kinase 14