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The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces
D R Brown1, C A Thomas, S P Deb
1Department of Microbiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284, USA.
Abstract:
The human oncoprotein MDM2 (hMDM2) overexpresses in various human tumors. If amplified, the mdm2 gene can enhance the tumorigenic potential of murine cells. Here, we present evidence to show that the full-length human or mouse MDM2 expressed from their respective cDNA can inhibit the G0/G1-S phase transition of NIH 3T3 and normal human diploid cells. The protein harbors more than one cell-cycle-inhibitory domain that does not overlap with the p53-interaction domain. Deletion mutants of hMDM2 that lack the cell-cycle-inhibitory domains can be stably expressed in NIH 3T3 cells, enhancing their tumorigenic potential. The tumorigenic domain of hMDM2 overlaps with the p53-interaction domain. Some tumor-derived cells, such as Saos-2, H1299 or U-2OS, are relatively insensitive to the growth-inhibitory effects of hMDM2. These observations suggest that hMDM2 overexpression in response to oncogenic stimuli would induce growth arrest in normal cells. Elimination or inactivation of the hMDM2-induced G0/G1 arrest may contribute to one of the steps of tumorigenesis.
Insights
The human MDM2 (hMDM2) oncoprotein inhibits normal cell growth by arresting the cell cycle. Loss of this function in tumor cells may drive cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The human oncoprotein MDM2 (hMDM2) is overexpressed in various human tumors.
- Amplification of the mdm2 gene can enhance tumor potential in murine cells.
Purpose of the Study:
- To investigate the cell-cycle regulatory functions of hMDM2.
- To identify domains within hMDM2 responsible for cell-cycle inhibition and tumorigenesis.
Main Methods:
- Expression of full-length human and mouse MDM2 from cDNA in NIH 3T3 and normal human diploid cells.
- Analysis of cell-cycle phase transition (G0/G1-S).
- Construction and expression of hMDM2 deletion mutants.
Main Results:
- Full-length hMDM2 and mouse MDM2 inhibit the G0/G1-S phase transition in normal cells.
- hMDM2 contains cell-cycle inhibitory domains distinct from its p53-interaction domain.
- Deletion mutants lacking inhibitory domains enhanced tumorigenic potential in NIH 3T3 cells.
- The tumorigenic domain of hMDM2 overlaps with its p53-interaction domain.
- Some tumor cell lines showed insensitivity to hMDM2's growth-inhibitory effects.
Conclusions:
- hMDM2 overexpression induces growth arrest in normal cells.
- Inactivation of hMDM2-induced G0/G1 arrest is a potential step in tumorigenesis.
- The findings highlight hMDM2's dual role in cell-cycle regulation and tumor promotion.