Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner.
Mdm2 promotes ubiquitination of the tumor suppressor p53 and can function as an oncogene by largely downregulating p53. Although a p53-independent role of Mdm2 has been reported, the underlying mechanism remains unclear. In the present study, we indicated that Mdm2 is involved in p53-independent carcinogenesis via downregulation of pRB. Expression of pRB showed an apparent inverse correlation with Mdm2 expression in 30 patients with non-small cell lung cancer. There were some cases with the p53 mutations in which a high level of Mdm2 and a low level of pRB were expressed. Mdm2 promoted ubiquitination of pRB in cells without wild-type p53. Furthermore, pRB-mediated G1 arrest in a p53-deficient cell line, SRB1, was significantly enhanced by a mutant Mdm2 that lacks pRB ubiquitination activity. Soft-agar colony formation activity of p53-knockout MEF was increased by wild-type Mdm2 but not mutant Mdm2. These findings suggest that overexpression of Mdm2 can perturb a RB pathway regardless of the p53 gene status, promoting carcinogenesis.
Miwa
Seiichi
S
Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan.
Uchida
Chiharu
C
Kitagawa
Kyoko
K
Hattori
Takayuki
T
Oda
Toshiaki
T
Sugimura
Haruhiko
H
Yasuda
Hideyo
H
Nakamura
Hirotoshi
H
Chida
Kingo
K
Kitagawa
Masatoshi
M
D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009687:Nuclear Proteins; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D018797:Cell Cycle Proteins; C416925:EID1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2