The cell cycle inhibitor p15^INK4b is frequently inactivated by homozygous deletion together with p16^INK4a and p19^ARF in some types of tumors. Although the tumor suppressor capability of p15^INK4b is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16^INK4aalterations. Here we show that, in vitro, p15^INK4b is a strong inhibitor of cellular transformation by Ras. Surprisingly, p15^INK4bis induced in cultured cells by oncogenic Ras to an extent similar to that of p16^INK4a, and their expression is associated with premature G₁ arrest and senescence. Ras-dependent induction of these two INK4 genes is mediated mainly by the Raf-Mek-Erk pathway. Studies with activated and dominant negative forms of Ras effectors indicate that the Raf-Mek-Erk pathway is essential for induction of both the p15^INK4band p16^INK4a promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response. Our results indicate that p15^INK4b, by itself, is able to stop cell transformation by Ras and other oncogenes such as Rgr (a new oncogene member of the Ral-GDS family, whose action is mediated through Ras). In fact, embryonic fibroblasts isolated from p15^INK4b knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15^INK4b-deficient mouse embryo fibroblasts are more sensitive than wild-type cells to transformation by a combination of the Rgr and E1A oncogenes. The cell cycle inhibitor p15^INK4b is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.