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Molecular and Cellular Biology, April 2000, p. 2915-2925, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b

Marcos Malumbres,dagger Ignacio Pérez De Castro, María I. Hernández, María Jiménez, Teresa Corral, and Angel Pellicer*

Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, New York 10016

Received 26 July 1999/Returned for modification 13 September 1999/Accepted 27 January 2000

The cell cycle inhibitor p15INK4b is frequently inactivated by homozygous deletion together with p16INK4a and p19ARF in some types of tumors. Although the tumor suppressor capability of p15INK4b is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16INK4a alterations. Here we show that, in vitro, p15INK4b is a strong inhibitor of cellular transformation by Ras. Surprisingly, p15INK4b is induced in cultured cells by oncogenic Ras to an extent similar to that of p16INK4a, 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 p15INK4b and p16INK4a promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response. Our results indicate that p15INK4b, 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 p15INK4b knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15INK4b-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 p15INK4b is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.

* Corresponding author. Mailing address: Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, 550 First Ave., New York, NY 10016. Phone: (212) 263-5342. Fax: (212) 263-8211. E-mail: pellia01{at}mcrcr.med.nyu.edu.

dagger Present address: Centro Nacional de Investigaciones Oncológicas Carlos III, Crta. Majadahonda-Pozuelo, 28220 Majadahonda, Madrid, Spain.

Molecular and Cellular Biology, April 2000, p. 2915-2925, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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