Suppression of c-ras transformation by GTPase-activating protein.
The ras genes are required for normal cell growth and mediate transformation by oncogenes encoding protein tyrosine kinases. Normal ras can transform cells in vitro and in vivo, but mutationally activated ras does so much more efficiently, and highly transforming mutant versions of ras have been isolated from a variety of human and animal tumours. The ras genes encode membrane-associated, guanine nucleotide-binding proteins that are active when GTP is bound and inactive when GDP is bound. The slow intrinsic GTPase activity of normal mammalian Ras proteins can be greatly accelerated by the GTPase-activating protein (GAP), which is predominantly cytoplasmic. This activity of GAP, which can increase with cell density in contact-inhibited cells, suggests that it functions as a negative, upstream regulator of ras. Other studies, however, show that GAP interacts with a region of ras-encoded protein implicated in ras effector function, which raises the possibility that GAP might also be a downstream target of ras. Mutationally activated ras-encoded proteins also interact with GAP, although they are resistant to its catalytic activity. In an attempt to define the role of GAP in ras-mediated transformation, we examined the effects on transformation of normal or mutant ras when cells overexpress GAP. We found that GAP suppresses transformation of NIH 3T3 cells by normal Ha-ras (c-ras) but does not inhibit transformation by activated Ha-ras (v-ras). These results support the hypothesis that GAP functions as a negative regulator of normal ras and make it unlikely that GAP alone is the ras target.
Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland 20892.
K
K
Zhang
J E
JE
DeClue
W C
WC
Vass
A G
AG
Papageorge
F
F
McCormick
D R
DR
Lowy
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation; D011905:Genes, ras; D051379:Mice; D009154:Mutation; D010957:Plasmids; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015183:Restriction Mapping; D013489:Suppression, Genetic; D014162:Transfection; D020703:ras GTPase-Activating Proteins
D020690:GTPase-Activating Proteins; D011506:Proteins; D020703:ras GTPase-Activating Proteins