Inhibition of apoptosis after thymineless stress is conferred by oncogenic K-Ras in colon carcinoma cells.
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.
Houghton
J A
JA
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Ebanks
R
R
Harwood
F G
FG
Tillman
D M
DM
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
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D013936:Thymidine