Journal Article

H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21 super(WAF1)-dependent mechanism

Lopez-Ilasaca, MA, Martinez, C, Delgado, MD, Vaque, JP, Arozarena, I, Crespo, P, Leon, J

2000

Overview

Mutated ras genes are frequently found in human cancer. However, it has been shown that oncogenic ras inhibits growth of primary cells, through pathways involving p53 and the cell cycle inhibitors p16 super(INK4a) and p19 super(ARF). We have analysed the effect of the ectopic expression of the three mammalian ras genes on the proliferation of K562 leukemia cells, which are deficient for p53, p16 super(INK4a), p15 super(INK4b) and p19 super(ARF) genes. We have found that high expression levels of both wild-type and oncogenic H-, K- and N-ras inhibit the clonogenic growth of K562 cells. Induction of H-rasV12 expression in K562 transfectants retards growth and this effect is accompanied with an increase of p21 super(WAF1) mRNA and protein levels. Furthermore, p21 super(WAF1) promoter is activated potently by oncogenic ras and less pronounced by wild-type ras. This induction is p53-independent since a P21 super(WAF1) promoter devoid of the p53 responsive elements is still activated by Ras. Finally, inhibition of p21 super(WAF1) expression by an antisense construct partially overcomes the growth inhibitory action of oncogenic H-ras. Altogether, these results indicate that the antiproliferative effect of ras in myeloid leukemia cells is associated to the induction of p21 super(WAF1) expression and suggest the existence of p19 super(ARF) and p16 super(INK4a)-independent pathways for ras-mediated growth inhibition.

• Subject: H-ras gene / K-ras gene / N-ras gene / p21 protein / Waf1 gene