title: 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.
abstract: The dbl family of oncogenes encodes a large, structurally related, family of growth-regulatory molecules that possess guanine nucleotide exchange factor activity for specific members of the Rho family of Ras-related GTPases. We have evaluated matched sets of weakly and strongly transforming versions of five Dbl family proteins (Lfc, Lsc, Ect2, Dbl, and Dbs) to determine their ability to stimulate signaling pathways that are activated by Rho family proteins. We found that the transforming potential of this panel did not correlate directly with their ability to activate Jun NH2-terminal kinase, p38/Mpk2, serum response factor, or c-Jun. In contrast, transient stimulation of transcription from the cyclin D1 promoter provided a strong correlation with transforming potential, and we found constitutive up-regulation of cyclin D1 protein in Dbl family protein-transformed cells. In addition, we observed that at least two Dbl family members (Lfc and Ect2) induced changes in the actin cytoskeleton and exhibited nuclear signaling profiles that are consistent with a broader range of in vivo substrate utilization than is predicted from their in vitro exchange specificities. In summary, although Dbl family proteins exhibit signaling profiles that are consistent with their in vivo activation of Rho proteins, stimulation of cyclin D1 transcription is the only activity that correlates with transforming potential, thus suggesting that deregulated cell cycle progression may be important for Dbl family protein transformation.
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7038, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Westwick
authors.forename: R J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Q T
authors.initials: QT
authors.lastname: Lambert
authors.forename: M
authors.initials: M
authors.lastname: Symons
authors.forename: R G
authors.initials: RG
authors.lastname: Pestell
authors.forename: C J
authors.initials: CJ
authors.lastname: Der
authors.forename: I P
authors.initials: IP
authors.lastname: Whitehead
mesh_terms: D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D026362:Serum Response Factor; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000199:Actins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D016755:Proto-Oncogene Proteins c-jun; D015682:Retroviridae Proteins, Oncogenic; D026362:Serum Response Factor; D000099190:MAP-Kinase-Activated Kinase 2; C512843:Mcf2 protein, mouse