A TRANSCRIPTIONAL CROSS–TALK BETWEEN RhoA AND c–Myc INHIBITS THE RhoA/Rock–DEPENDENT CYTOSKELETON

The GTPase RhoA participates in a number of cellular processes, including cytoskeletal organization, mitogenesis and tumorigenesis. We have previously shown that the transforming activity of an oncogenic version of RhoA (Q63L mutant) was highly dependent on the transcriptional factor c–Myc. In contrast to these positive effects in the RhoA route, we show here that c–Myc affects negatively the F–actin cytoskeleton induced by RhoA(Q63L) and its downstream effector, the serine/threonine kinase Rock. This effect entails the activation of a transcriptional program that requires synergistic interactions with RhoA–derived signals and that includes the upregulation of the GTPase Cdc42 and its downstream element Pak1 as well as the repression of specific integrin subunits. The negative effects of c–Myc in the F–actin cytoskeleton are eliminated by the establishment of cell–to–cell contacts, an effect associated with the rescue of Pak1 and integrin levels at the post–transcriptional and transcriptional levels, respectively. These results reveal the presence of a hitherto unknown signaling feed–back loop between RhoA and c–Myc oncogenes that can contribute to maintain fluid cytoskeletal dynamics in cancer cells.