AUTOCRINE GROWTH AND ANCHORAGE INDEPENDENCE - 2 COMPLEMENTING JUN-CONTROLLED GENETIC PROGRAMS OF CELLULAR-TRANSFORMATION

Cellular transformation can be achieved by constitutive activation of growth-regulatory signaling pathways, which, in turn, activate nuclear transcription factors thought to execute a transformation-specific pr ogram of gene expression. Members of the dimeric transcription factor family AP-1 are at the receiving end of such growth-regulating pathway s and the viral form of the AP-1 subunit Jun establishes one important aspect of transformation in chick embryo fibroblasts (CEFs): enhanced growth in agar and in low serum. Enhanced Jun activity is likely to t arget several different genetic programs as Sun forms heterodimers wit h one of several members of the Fos and ATF2 subfamilies, resulting in transcription factors with different sequence specificities. To ident ify the programs relevant for transformation, we have reduced the comp lexity of AP-1 factors by constructing Jun bZip mutants that can effic iently dimerize and transactivate with only a restricted set of partne r subunits. Upon introduction into CEFs, a Jun mutant selective for th e Fos family induced anchorage-independent growth but no growth factor -independence. In contrast, a c-Tun mutant with preference for ATF2-li ke proteins caused growth factor-independence, but no growth in agar. Coexpression of both mutants reestablished the combined transformation program as induced by wild-type Jun. These data show that Jun-depende nt cell transformation can be resolved into at least two distinct and independent processes, anchorage and growth factor independence, obvio usly triggered by two classes of Jun heterodimers likely regulating di fferent sets of target genes.