Differential effect of Rac and Cdc42 on p38 kinase activity and cell cycleprogression of nonadherent primary mouse fibroblasts

The Rho GTPases play an important role in transducing signals linking plasm a membrane receptors to the organization of the cytoskeleton and also regul ate gene transcription. Here, we show that expression of constitutively act ive Ras or Cdc42, but not RhoA, RhoG;, and Rad, is sufficient to cause anch orage-independent cell cycle progression of mouse embryonic fibroblasts, Ho wever, in anchorage free conditions, whereas activation of either Cdc42 or Ras results in cyclin A transcription and cell cycle progression, Cdc42 is not required for Ras-mediated cyclin A induction, and the two proteins act in a synergistic manner in this process. Surprisingly, the ability of Cdc42 to induce p38 MAPK activity-in suspended mouse embryonic fibroblast was im paired. Moreover, inhibition of p38 activity allowed Rad to induce: anchora ge-independent cyclin A transcription, indicating that p38 MAPK has an inhi bitory function on cell cycle progression of primary fibroblasts. Finally, a Rac mutant, which is unable to induce lamellipodia and focal complex form ation, promoted cyclin A transcription in the presence of SB203580, suggest ing that the organization of the cytoskeleton is not required for anchorage -independent proliferation. This demonstrates a novel function for Cdc42, d istinct from that of Rad, in the control of cell proliferation.