Autocrine growth and anchorage independence: two 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 program of gene expression. Members of the dimeric transcription factor family AP-1 are at the receiving end of such growth-regulating pathways 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 target several different genetic programs as Jun forms heterodimers with one of several members of the Fos and ATF2 subfamilies, resulting in transcription factors with different sequence specificities. To identify the programs relevant for transformation, we have reduced the complexity of AP-1 factors by constructing Jun bZip mutants that can efficiently dimerize and transactivate with only a restricted set of partner subunits. Upon introduction into CEFs, a Jun mutant selective for the Fos family induced anchorage-independent growth but no growth factor-independence. In contrast, a c-Jun mutant with preference for ATF2-like 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-dependent cell transformation can be resolved into at least two distinct and independent processes, anchorage and growth factor independence, obviously triggered by two classes of Jun heterodimers likely regulating different sets of target genes.
van Dam
H
H
Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, University of Leiden, 2300 RA Leiden, The Netherlands.
Huguier
S
S
Kooistra
K
K
Baguet
J
J
Vial
E
E
van der Eb
A J
AJ
Herrlich
P
P
Angel
P
P
Castellazzi
M
M
D051698:Activating Transcription Factor 2; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D019281:Dimerization; D005816:Genetic Complementation Test; D006367:HeLa Cells; D006801:Humans; D016350:Leucine Zippers; D051379:Mice; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors