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Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner.

Miwa S, Uchida C, Kitagawa K, Hattori T, Oda T, Sugimura H, Yasuda H, Nakamura H, Chida K, Kitagawa M

Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan.

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.

Published 26 December 2005 in Biochem Biophys Res Commun, 340(1): 54-61.
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