The central acidic domain of MDM2 is critical in inhibition of retinoblastoma-mediated suppression of E2F and cell growth.
Retinoblastoma (Rb) protein is a paradigm of tumor suppressors. Inactivation of Rb plays a critical role in the development of human malignancies. MDM2, an oncogene frequently found amplified and overexpressed in a variety of human tumors and cancers, directly interacts and inhibits the p53 tumor suppressor protein. In addition, MDM2 has been shown to stimulate E2F transactivation activity and promote S-phase entry independent of p53, yet the mechanism of which is still not fully understood. In this study, we demonstrate that MDM2 specifically binds to Rb C-pocket and that the central acidic domain of MDM2 is essential for Rb interaction. In addition, we show that overexpression of MDM2 reduces Rb-E2F complexes in vivo. Moreover, the ectopic expression of the wild type MDM2, but not mutant MDM2 defective in Rb interaction, stimulates E2F transactivation activity and inhibits Rb growth suppression function. Taken together, these results suggest that MDM2-mediated inhibition of Rb likely contributes to MDM2 oncogenic activity.
Sdek
Patima
P
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Ying
Haoqiang
H
Zheng
Hongwu
H
Margulis
Alexander
A
Tang
Xiaoren
X
Tian
Kui
K
Xiao
Zhi-Xiong Jim
ZX
D000595:Amino Acid Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D050684:E2F Transcription Factors; D017930:Genes, Reporter; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase; D005978:Glutathione