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The Growth Arrest Function of the Human Oncoprotein Mouse Double Minute-2 Is Disabled by Downstream Mutation in Cancer Cells

Department of Biochemistry and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia

Requests for reprints: Swati P. Deb, Department of Biochemistry, Sanger Hall, P.O. Box 980614, 1101 East Marshall Street, MCV/Virginia Commonwealth University, Richmond, VA 23298-0614. Phone: 804-828-9541; Fax: 804-827-1427; E-mail: spdeb{at}hsc.vcu.edu.

We have reported earlier that ectopic expression of mouse double minute-2 (MDM2) induces G₁ arrest in normal cells. To explain occasional overexpression of MDM2 in cancer cells, we searched for deletion or substitution mutation in the growth suppressor domains of MDM2 in several breast cancer cell lines that overexpress the oncoprotein. Our results suggest the absence of alteration (deletion or substitution) in the open reading frame of MDM2 transcripts in such cells. Because the breast cancer cell line MCF-7 overexpresses MDM2, we isolated the full-length MDM2 transcript from this cell line. The MDM2 cDNA synthesized from transcripts isolated from MCF-7 cells induced inhibition of G₁ to S phase transition in normal human diploid cells such as WI38, suggesting that the genetic alterations in breast cancer cells that overexpress MDM2 disable the growth arrest function of the oncoprotein. Consistently, overexpression of full-length MDM2 in MCF-7 cells over its high endogenous level did not inhibit G₁-S transition efficiently. Although MDM2 overexpression was accompanied by CDK4 overexpression or absence of cdk4 inhibitor p16 in most breast cancer cells, we found remarkably high levels of cyclin A rather than cyclin E in these cells. Ectopic expression of cyclin A released MDM2-mediated inhibition of G₁-S transition in normal human diploid WI38 cells. We propose that cancer cells expressing high levels of cyclin A escape MDM2-mediated G₁ arrest, which may account for a selective growth advantage over normal cells.

Key Words: MDM2 • G₁ arrest • Cyclin A • p16 • Tumorigenesis

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