Mr. Johnson et al., NEUROFIBROMIN CAN INHIBIT RAS-DEPENDENT GROWTH BY A MECHANISM INDEPENDENT OF ITS GTPASE-ACCELERATING FUNCTION, Molecular and cellular biology, 14(1), 1994, pp. 641-645
The NF1 gene, which is altered in patients with type 1 neurofibromatos
is, has been postulated to function as a tumor suppressor gene. The NF
1 protein product neurofibromin stimulates the intrinsic GTPase activi
ty of active GTP-bound Ras, thereby inactivating it. Consistent with a
tumor suppressor function, we have found that the introduction of NF1
in melanoma cell lines that are deficient in neurofibromin inhibited
their growth and induced their differentiation. In addition, overexpre
ssion of neurofibromin in NIH 3T3 cells was growth inhibitory but did
not alter the level of GTP . Ras in the cells. Transformation by v-ras
, whose protein product is resistant to GTPase stimulation by neurofib
romin, was inhibited in a cell line overexpressing neurofibromin, whil
e transformation by v-raf was not altered. The results demonstrate tha
t NF1 is a tumor suppressor gene that can inhibit Ras-dependent growth
by a regulatory mechanism that is independent of neurofibromin's abil
ity to stimulate Ras GTPase.