Reduced hepatic tumor incidence in cyclin G1-deficient mice.
Cyclin G1 is a transcriptional target of the tumor suppressor p53, and its expression is increased after DNA damage. Recent data show that cyclin G1 can regulate the levels of p53 by a mechanism that involves dephosphorylation of Mdm2 by protein phosphatase 2A. To understand the biologic role of cyclin G1, we have generated cyclin G1-deficient mice. In agreement with previous results, we showed that these mice develop normally, and that proliferation and induction of cellular senescence in cyclin G1-deficient mouse embryo fibroblasts are indistinguishable from wild-type fibroblasts. However, we found that the p53 levels in the cyclin G1-deficient mice are 2-fold higher that in wild-type mice. Moreover, we showed that treatment of mice with the alkylating agent 1,4-bis[N,N'-di(ethylene)-phosphamide]piperazine (Dipin), followed by partial hepatectomy, decreased G1-S transition in cyclin G1-null hepatocytes as compared with wild type. Finally, we found a significant decrease in tumor incidence, mass, and malignancy in both male and female cyclin G1-null mice after treatment with the potent hepatocarcinogen N-diethylnitrosamine. Taken with recent published data, our results suggest that cyclin G1, together with Mdm2, constitute a part of a negative feedback system that attenuates the activity of p53. In conclusion, our data suggest that the decreased tumor susceptibility after loss of cyclin G1 function is caused by the increased tumor suppressor action of p53.
Jensen
Michael Rugaard
MR
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Factor
Valentina M
VM
Fantozzi
Anna
A
Helin
Kristian
K
Huh
Chang-Goo
CG
Thorgeirsson
Snorri S
SS
D000477:Alkylating Agents; D000818:Animals; D002455:Cell Division; D016922:Cellular Senescence; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000172:deficiency* / Q000235:genetics; D004249:DNA Damage; D004052:Diethylnitrosamine; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology; D006720:Homozygote; D015994:Incidence; D008113:Liver Neoplasms / Q000139:chemically induced / Q000453:epidemiology* / Q000517:prevention & control; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000477:Alkylating Agents; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine