Transformation by ras modifies AP1 composition and activity.
The Ras proteins play a central role in regulating cell growth and their mutation can lead to abnormal proliferation. To analyse the potential link betwen AP1 activity, encoded by members of the jun and fos gene families, and Ras-mediated cellular transformation, we have studied several NIH3T3 clones which overexpress the Ha-Ras or Ki-Ras oncogenes. These transformed fibroblasts accumulated higher levels of cJun, JunB, Fra1 and Fra2 proteins relative to their normal counterparts. They also displayed increased AP1 DNA binding activity which was predominantly composed of cJun and Fra1 containing dimers. Following serum stimulation of Ras clones, the elevated levels of cJun and Fral remained steady, while the induction of JunB and Fra2 was partially attenuated. Moreover, deregulated Ras signaling resulted in a complete loss of the serum inducibility of cFos and FosB. Ectopic co-expression of cJun and Fra1 in NIH3T3 fibroblasts led to a transformed phenotype, attenuation of cFos serum inducibility, increased AP1 activity and Cyclin D1 accumulation, all characteristics of oncogenic Ras expressing cells. These results demonstrate that cJun and Fra1 are crucial mediators of the Ras-transformation process.
Mechta
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Unité des Virus Oncogenes, URA 1644 du CNRS, Département des Biotechnologies, Institut Pasteur, Paris, France.
Lallemand
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Pfarr
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CM
Yaniv
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M
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019938:Cyclin D1; D016213:Cyclins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D051921:Fos-Related Antigen-2; D051379:Mice; D015513:Oncogene Proteins / Q000032:analysis; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000032:analysis* / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis; D018631:ras Proteins / Q000502:physiology*; D000099169:Fos-Related Antigen 1
D019938:Cyclin D1; D016213:Cyclins; D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D015513:Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D018631:ras Proteins; D000099169:Fos-Related Antigen 1; C497873:Fosl2 protein, mouse