title: Correlation of genetic instability and apoptosis in the presence of oncogenic Ki-Ras.
abstract: The product of the ras proto-oncogene has been implicated as an essential signal transducer, involved in a variety of biological or pathological activities, including apoptosis. The aim of this investigation was to further explore the mechanisms of apoptosis triggered by Ras. Stable expression of constitutively-activated (v)-Ki-Ras in Balb/c-3T3 mouse fibroblasts resulted in a loss of G1 arrest in response to treatments which induced cell cycle arrest in the parental Balb/c-3T3 cells, accompanied by decreased expression of the p53 tumor suppressor protein and the GADD45 gene, the product of which is involved in DNA repair, and deregulated expression of the MDM-2 gene, the product of which can regulate p53 expression. Ki-Ras expression also increased the frequency of PALA-selectable CAD gene amplification, and paradoxically the susceptibility to PALA-induced apoptosis. After persistent serum-starvation, cells expressing the activated ras gene lost clonogenic potential, indicating impaired capability for genetic repair in the cells. Taken together, these data suggest that activated Ki-ras may confer genetic instabilty upon cells, possibly through interference with tumor suppressors, such as p53. While this instability may facilitate adaptation to environmental stresses, this instability in the genome also renders cells containing activated ras genes intrinsically more susceptible to programmed cell death, possibly by accumulation of undesirable or lethal genetic events during the process of tumor development.
authors.affiliation: Cancer Research Center, Boston University School of Medicine, Massachusetts 02118, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Liou
authors.forename: L W
authors.initials: LW
authors.lastname: Forman
authors.forename: D V
authors.initials: DV
authors.lastname: Faller
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001221:Aspartate Carbamoyltransferase / Q000235:genetics; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics; D003114:Colony-Forming Units Assay; D016895:Culture Media, Serum-Free; D004260:DNA Repair / Q000235:genetics; D004080:Dihydroorotase / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D005784:Gene Amplification; D015870:Gene Expression; D016158:Genes, p53; D011905:Genes, ras; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics; D009687:Nuclear Proteins; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D015398:Signal Transduction; D000097642:GADD45 Proteins
chemical_list: D001221:Aspartate Carbamoyltransferase; D001224:Aspartic Acid; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D016895:Culture Media, Serum-Free; D004080:Dihydroorotase; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D010746:Phosphonoacetic Acid; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D000097642:GADD45 Proteins; C033626:CAD trifunctional enzyme; C013195:sparfosic acid; C497207:Mdm2 protein, mouse