Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway

Apoptosis is a normal physiological process which eliminates cells that do not receive adequate extracellular signals. One of the pathways signalling apoptosis is controlled by the small GTPases of the Rho family, also involv ed in cell proliferation, differentiation and motility, Another major apopt osis signalling pathway involves the p53 tumour suppressor which is activat ed by a variety of stress and mediates growth arrest or apoptosis in normal cells. We show here that upon detachment from the extracellular matrix, fi broblasts undergo rapid apoptosis that can be rescued by constitutive activ ation of Rad and Cdc42Hs GTPases, Conversely, inhibition of Rad and Cdc42Hs efficiently triggers apoptosis in adherent cells. Interestingly, apoptosis is not observed in p53(-/-) cells either cultured in suspension or inhibit ed for Rad and Cdc42Hs activity. Moreover, Rad and Cdc42Hs extinction in no rmal cells activates endogenous p53, Using specific inhibitors of MAPK path ways, we demonstrate that, in our experimental system, p38 signals survival , while ERK activity is required for apoptosis, Our data constitute the fir st demonstration that Rad and Cdc42Hs control pathways that require simulta neous signalling through MAPK ERK and p53 to induce apoptosis.