Abstract
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 p16INK4a and p19ARF. 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, p16INK4a, p15INK4b and p19ARF 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 p21WAF1 mRNA and protein levels. Furthermore, p21WAF1 promoter is activated potently by oncogenic ras and less pronounced by wild-type ras. This induction is p53-independent since a p21WAF1 promoter devoid of the p53 responsive elements is still activated by Ras. Finally, inhibition of p21WAF1 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 p21WAF1 expression and suggest the existence of p19ARF and p16INK4a-independent pathways for ras-mediated growth inhibition.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Barbacid M. . 1989 Annu. Rev. Biochem. 56: 779–827.
Beaupre DM and Kurzrock R. . 1999 J. Clin. Oncol. 17: 1071–1079.
Chi S, Kitanaka Ch, Noguchi K, Mochizuki T, Nagashima Y, Shirouzu M, Fujita H, Yoshida M, Chen W, Asai H, Himeno M, Yokoyama S and Kuchino Y. . 1999 Oncogene 18: 2281–2290.
Crespo P, Xu N, Simonds WF and Gutkind JS. . 1994a Nature 369: 418–420.
Crespo P, Xu N, Daniotti JL, Troppmair J, Rapp UR and Gutkind JS. . 1994b J. Biol. Chem. 269: 21103–21109.
Delgado MD, Quincoces AF, Gomez-Casares MT, Martinez CA, Cuadrado MA, Richard C and Leon J. . 1992 Cancer Res. 52: 5979–5984.
Della Valle V, Duro D, Bernard O and Larsen CJ. . 1997 Oncogene 15: 2475–2481.
Downward J. . 1998 Curr. Opin. Genet. Dev. 8: 49–54.
El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.
Esteve P, Embade N, Perona R, Jimenez B, del Peso L, Leon J, Arends M, Miki T and Lacal JC. . 1998 Oncogene 17: 1855–1869.
Fang L, Igarashi M, Leung J, Sugrue MM, Lee SW and Aaronson SA. . 1999 Oncogene 18: 2789–2797.
Gartel AL and Tyner AL. . 1999 Exp. Cell Res. 246: 280–289.
Hawley RG, Fong AZ, Ngan BY and Hawley TS. . 1995 Oncogene 11: 1113–1123.
Juan G, Ardelt B, Li X, Mikulski SM, Shogen K, Ardelt W, Mittelman A and Darzynkiewicz Z. . 1998 Leukemia 12: 1241–1248.
Koskinen PJ, Ayer DE and Eisenman RN. . 1995 Cell Growth Differ. 6: 623–629.
Law JC, Ritke MK, Yalowich JC, Leder GH and Ferrell RE. . 1993 Leuk. Res. 17: 1045–1050.
León J and Pellicer A. . 1993 In: The ras Superfamily of GTPases. Lacal JC and McCormick F. (eds).. CRC Press: Boca Raton pp. 3–36.
Lerga A, Belandia B, Delgado MD, Cuadrado MA, Richard C, Ortiz JM, Martin-Perez J and Leon J. . 1995 Biochem. Biophys. Res. Commun. 215: 889–895.
Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M and Lowe SW. . 1998 Genes Dev. 12: 3008–3019.
Lloyd AC, Obermuller F, Staddon S, Barth CF, McMahon M and Land H. . 1997 Genes Dev. 11: 663–677.
Lloyd AC. . 1998 Curr. Opin. Genet. Dev. 8: 43–48.
Maher J, Baker D, Dibb N and Roberts I. . 1996 Leukemia 10: 83–90.
Malumbres M and Pellicer A. . 1998 Front. Biosci. 3: 887–912.
Morgenstern JP and Land H. . 1990 Nucl. Acids Res. 18: 3587–3596.
Ogawa S, Hirano N, Sato N, Takahashi T, Hangaishi A, Tanaka K, Kurokawa M, Tanaka T, Mitani Ki, Yazaki Y and Hirai H. . 1994 Blood 84: 2431–2451.
Olson MF, Paterson HF and Marshall Ch J. . 1998 Nature 394: 295–299.
Otsuki T, Clark HM, Wellmann A, Jaffe ES and Raffeld M. . 1995 Cancer Res. 55: 1436–1440.
Palmero I, Pantoja C and Serrano M. . 1998 Nature 395: 125–126.
Pantoja C and Serrano M. . 1999 Oncogene 18: 4974–4982.
Pierce JH and Aaronson SA. . 1985 Mol. Cell. Biol. 5: 667–674.
Quincoces AF, Polanco I, Thomson T and Leon J. . 1997 FEBS Lett. 416: 317–323.
Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW. . 1997 Cell 88: 593–602.
Sewing A, Wiseman B, Lloyd AC and Land H. . 1997 Mol. Cell. Biol. 17: 5588–5597.
Sharpless NE and DePinho RA. . 1999 Curr. Opin. Genet. Develop. 9: 22–30.
Teramoto H, Crespo P, Coso OA, Igishi T, Xu N and Gutkind JS. . 1996 J. Biol. Chem. 271: 25731–25744.
Todd AV and Iland HJ. . 1991 Leuk. Lymph. 3: 293–300.
Vonlanthen S, Heighway J, Tschan MP, Borner MM, Altermatt HJ, Kappeler A, Tobler A, Fey MF, Thatcher N, Yarbrough WG and Betticher DC. . 1998 Oncogene 17: 2779–2785.
Watzinger F, Gaiger A, Karlic H, Becher R, Pillwein K and Lion T. . 1994 Cancer Res. 54: 3934–3938.
Woods D, Parry D, Cherwinski H, Bosch E, Lees E and McMahon M. . 1997 Mol. Cell. Biol. 17: 5598–5611.
Zhu J, Woods D, McMahon M and Bishop JM. . 1998 Genes Dev. 12: 2997–3007.
Acknowledgements
We thank Rosa Blanco for expert technical assistance and Mariano Barbacid, Amancio Carnero, Jean de Gunzburg, Päivi Koskinen, Moshe Oren, Manuel Serrano and Robert Weinberg for plasmids. We are also indebted to Manuel Serrano for helpful discussions. This work has been supported by grants PM98-0109 from Spanish Ministry of Education and Culture and Biomed 96-3532 from European Community (J León) and from Fundacion Marcelino Botin (P Crespo).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Delgado, M., Vaqué, J., Arozarena, I. et al. H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism. Oncogene 19, 783–790 (2000). https://doi.org/10.1038/sj.onc.1203384
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203384
Keywords
This article is cited by
-
Convergence of Logic of Cellular Regulation in Different Premalignant Cells by an Information Theoretic Approach
BMC Systems Biology (2011)
-
Signal transduction pathways that contribute to myeloid differentiation
Leukemia (2007)
-
Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes
Oncogene (2005)
-
A retroviral library genetic screen identifies IRF-2 as an inhibitor of N-ras-induced growth suppression in leukemic cells
Oncogene (2005)
-
Ha-RasG12V induces senescence in primary and immortalized human esophageal keratinocytes with p53 dysfunction
Oncogene (2004)