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The growth arrest function of the human oncoprotein mouse double minute-2 is disabled by downstream mutation in

Ruizhe Zhou1, Rebecca Frum, Sumitra Deb

  • 1Department of Biochemistry and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298-0614, USA.

Cancer Research
|March 9, 2005
PubMed

Insights

Overexpressed mouse double minute-2 (MDM2) normally arrests cell growth. In breast cancer, high cyclin A levels override MDM2

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Mouse double minute-2 (MDM2) oncoprotein overexpression is observed in some cancers.
  • MDM2 typically induces G1 cell cycle arrest in normal cells.
  • The mechanism by which cancer cells evade MDM2-mediated growth arrest is not fully understood.

Purpose of the Study:

  • To investigate the functional status of MDM2 in breast cancer cells with high MDM2 expression.
  • To identify factors contributing to the escape from MDM2-induced G1 arrest in cancer cells.

Main Methods:

  • Analysis of MDM2 gene and transcript sequences in breast cancer cell lines.
  • Functional assays of MDM2-mediated G1 arrest in normal human diploid cells (WI38).
  • Assessment of cell cycle regulatory proteins, including cyclins and CDK inhibitors, in breast cancer cells.

Main Results:

  • No mutations or alterations were found in the MDM2 open reading frame of overexpressing breast cancer cells.
  • MDM2 transcripts from MCF-7 cells retained the ability to induce G1 arrest in normal cells, indicating functional MDM2.
  • Overexpression of MDM2 in MCF-7 cells did not efficiently inhibit G1-S transition.
  • High levels of Cyclin A, not Cyclin E, were observed in MDM2-overexpressing breast cancer cells.
  • Ectopic expression of Cyclin A rescued normal cells from MDM2-mediated G1 arrest.

Conclusions:

  • Genetic alterations in breast cancer cells do not disable MDM2's growth arrest function.
  • High Cyclin A levels in cancer cells enable escape from MDM2-mediated G1 arrest.
  • This escape mechanism may confer a selective growth advantage to cancer cells.

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