TRANSFORMING POTENTIAL OF DBL FAMILY PROTEINS CORRELATES WITH TRANSCRIPTION FROM THE CYCLIN D1 PROMOTER BUT NOT WITH ACTIVATION OF JUN NH2-TERMINAL KINASE, P38 MPK2, SERUM RESPONSE FACTOR, OR C-JUN/

The dbl family of oncogenes encodes a large, structurally related, fam ily of growth-regulatory molecules that possess guanine nucleotide exc hange factor activity for specific members of the Rho family of Pas-re lated GTPases. We have evaluated matched sets of weakly and strongly t ransforming versions of five Dbl family proteins (Lfc, Lsc, Ect2, Dbl, and Dbs) to determine their ability to stimulate signaling pathways t hat are activated by Rho family proteins, We found that the transformi ng potential of this panel did not correlate directly with their abili ty to activate Jun NH2-terminal kinase, p38/Mpk2, serum response facto r, or c-Jun. In contrast, transient stimulation of transcription from the cyclin DI promoter provided a strong correlation with transforming potential, and we found constitutive up-regulation of cyclin D1 prote in in Dbl family protein-transformed cells, In addition, we observed t hat at least two Dbl family members (Lfc and Ect2) induced changes in the actin cytoskeleton and exhibited nuclear signaling profiles that a re consistent with a broader range of in vivo substrate utilization th an is predicted from their in vitro exchange specificities. In summary , although Dbl family proteins exhibit signaling profiles that are con sistent with their in vivo activation of Rho proteins, stimulation of cyclin D1 transcription is the only activity that correlates with tran sforming potential, thus suggesting that deregulated cell cycle progre ssion may be important for Dbl family protein transformation.