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The carcinogen 2‐acetylaminofluorene inhibits activation and nuclear accumulation of cyclin‐dependent kinase 2 in growth‐induced rat liver
Author(s) -
Lindeman Birgitte,
Skarpen Ellen,
Oksvold Morten P.,
Huitfeldt Henrik S.
Publication year - 2000
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(200003)27:3<190::aid-mc6>3.0.co;2-n
Subject(s) - 2 acetylaminofluorene , biology , cyclin dependent kinase 2 , cyclin dependent kinase , cyclin e , cyclin a , liver regeneration , cyclin , hepatocyte , kinase , carcinogen , cancer research , microbiology and biotechnology , biochemistry , cell cycle , protein kinase a , apoptosis , enzyme , in vitro , regeneration (biology) , microsome
Growth arrest in G 1 is a common cellular response to DNA damage. In the present study, liver regeneration was combined with continuous exposure for 2‐acetylaminofluorene (AAF) to study mechanisms of carcinogen‐induced growth arrest in vivo. Growth arrest of uninitiated hepatocytes is central for AAF‐induced promotion of premalignant lesions in rat liver. To characterize this growth arrest, we examined the activity of cyclin‐dependent kinase (Cdk) 2 in unexposed liver and in AAF‐exposed liver after growth induction by partial hepatectomy (PH). Rats were fed either a control diet or an AAF‐supplemented diet. After 7 d, a two‐third PH was performed and the animals were killed after 0, 12, 18, 24, and 36 h. Kinase assays showed that cyclin E– and Cdk2–associated activities were lower in AAF‐exposed liver than in unexposed liver after PH. Although the total cellular levels of cyclin E and Cdk2 were similar, cyclin E–Cdk2 assembly was markedly reduced. In unexposed hepatocytes, Cdk2 translocated to the nuclei after PH. Much of the nuclear Cdk2 was in a rapidly migrating form, presumably representing the Thr160‐phosphorylated form of Cdk2. In contrast, in AAF‐exposed liver both nuclear Cdk2 accumulation and Thr160‐phosphorylation of Cdk2 were reduced. Although p53 and p21 waf1/cip1 were induced by AAF, the binding of p21 to cyclin E and Cdk2 was not increased in growth arrested liver. In conclusion, hepatocyte growth arrest caused by AAF exposure was characterized by a lowered Cdk2 activity that was accompanied by a reduced assembly of cyclin E–Cdk2 complexes but not by binding of p21. Mol. Carcinog. 27:190–199, 2000. © 2000 Wiley‐Liss, Inc.