title: Inhibition of apoptosis after thymineless stress is conferred by oncogenic K-Ras in colon carcinoma cells.
abstract: Ras functions as a molecular switch for several downstream targets and may promote either apoptosis or survival dependent upon the cell system and stimulus. The functional significance of a transfected K-Ras oncogene in influencing apoptosis induced by thymineless stress was examined in a thymidylate synthase (TS)-deficient (TS-) colon carcinoma cell line derived from GC3/c1 after thymidine deprivation. Oncogenic K-Ras conferred survival in TS- K-Ras clones compared with TS- (untransfected) and TS- pCIneo (vector control). Previously, we had demonstrated that thymineless death involved signaling via Fas/FasL interactions. However, in the presence of oncogenic K-Ras, survival did not involve down-regulation of Fas or FasL expression but did involve members of the Bcl-2 family. Bcl-2 and Bax expression remained relatively constant during thymineless stress in all cell lines. Apoptosis in the presence of wild-type Ras correlated with up-regulated expression of Bak that did not occur in TS- K-Ras clones, whereas survival in these clones correlated with elevated expression of Bcl-xL. Thus, the Bak:Bcl-xL ratio was high in TS- and TS- pCIneo cells undergoing apoptosis, whereas the Bcl-xL:Bak ratio was high in TS- K-Ras clones exhibiting a survival response.
authors.affiliation: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Houghton
authors.forename: R
authors.initials: R
authors.lastname: Ebanks
authors.forename: F G
authors.initials: FG
authors.lastname: Harwood
authors.forename: D M
authors.initials: DM
authors.lastname: Tillman
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D009857:Oncogenes; D013936:Thymidine / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D013936:Thymidine