Autocrine growth and anchorage independence: two complementing Jun-controlled genetic programs of cellular transformation (original) (raw)

  1. Hans van Dam,
  2. Stéphanie Huguier,
  3. Klaas Kooistra,
  4. Joël Baguet,
  5. Emmanuel Vial,
  6. Alex J. van der Eb,
  7. Peter Herrlich,
  8. Peter Angel, and
  9. Marc Castellazzi
  10. Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, University of Leiden, 2300 RA Leiden, The Netherlands; Forschungszentrum Karlsruhe, Institute of Genetics, 76021 Karlsruhe, Germany; Unité de Virologie Humaine, Institut National de la Santé et de la Recherche Médicale (INSERM)-U412, Ecole Normale Supérieure, Lyon Cedex 07, France; Department of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Heidelberg, Germany

Abstract

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.

Footnotes