Complex effects of Ras proto-oncogenes in tumorigenesis.
Ras proteins have been found mutated in about one-third of human tumors. In vitro, Ras has been shown to regulate distinct and contradictory effects, such as cellular proliferation and apoptosis. Nonetheless, the effects that the wild-type protein elicits in tumorigenesis are poorly understood. Depending on the type of tissue, Ras proto-oncogenes appear to either promote or inhibit the tumor phenotype. In this report, we treated wild-type and N-ras knockout mice with 3-methylcholanthrene (MCA) to induce fibrosarcomas and found that MCA is more carcinogenic in wild-type mice than in knockout mice. After injecting different doses of a tumorigenic cell line, the wild-type mice exhibited a shorter latency of tumor development than the knockouts, indicating that there are N-ras-dependent differences in the stromal cells. Likewise, we have analyzed B-cell lymphomas induced by either N-methylnitrosourea or by the N-ras oncogene in mice that over-express the N-ras proto-oncogene and found that the over-expression of wild-type N-ras is able to increase the incidence of these lymphomas. Considered together, our results indicate that Ras proto-oncogenes can enhance or inhibit the malignant phenotype in vivo in different systems.
Diaz
Roberto
R
Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Lopez-Barcons
Lluis
L
Ahn
Daniel
D
Garcia-Espana
Antonio
A
Yoon
Andrew
A
Matthews
Jeremy
J
Mangues
Ramon
R
Perez-Soler
Roman
R
Pellicer
Angel
A
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000139:chemically induced / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008770:Methylnitrosourea; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics*; D000090063:Proto-Oncogene Mas
D002273:Carcinogens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D008770:Methylnitrosourea