THE TUMORIGENIC POTENTIAL AND CELL-GROWTH CHARACTERISTICS OF P53-DEFICIENT CELLS ARE EQUIVALENT IN THE PRESENCE OR ABSENCE OF MDM2

The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor pro tein and inhibits p53-mediated regulation of heterologous gene express ion. Recently, Mdm2 has been found to bind several other proteins that function to regulate cell cycle progression, including the EZF-1/DP1 transcription factor complex and the retinoblastoma tumor-suppressor p rotein, To determine whether Mdm2 plays a role in cell cycle control o r tumorigenesis that is distinct from its ability to modulate p53 func tion, we have examined and compared both the in vitro growth character istics of p53-deficient and Mdm2/p53-deficient fibroblasts, and the ra te and spectrum of tumor formation in p53-deficient and Mdm2/p53-defic ient mice, We find no difference between p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts either in their rate of proliferation in culture or in their survival frequency when treated with various ge notoxic agents, Cell cycle studies indicate no difference in the abili ty of the two cell populations to enter S phase when treated with DNA- damaging agents or nucleotide antimetabolites, and p53-deficient fibro blasts and Mdm2/p53-deficient fibroblasts exhibit the same rate of spo ntaneous immortalization following long-term passage in culture, Final ly, p53-dcficient mice and Mdm2/p53-deficient mice display the same in cidence and spectrum of spontaneous tumor formation in vivo. These res ults demonstrate that deletion of Mdm2 has no additional effect on cel l proliferation, cell cycle control, or tumorigenesis when p53 is abse nt.