Increased expression of G1 cyclins and cyclin-dependent kinases during tumor progression of chemically induced mouse skin neoplasms.
Cyclins and cyclin-dependent kinases (Cdks) are central to regulation of the cell cycle. Their abnormal expression may cause loss of cell-cycle control and result in autonomous cell growth, a critical feature of neoplasias. In this study, using immunoblotting, we analyzed the protein levels of several G1/S cyclins (cyclins D1, D2, D3, A, and E) and their respective Cdks (Cdk 2, 4, and 6) in 17 mouse squamous cell carcinomas (SCCs) and 18 mouse skin tumor cell lines. Overexpression of these cell cycle-related genes was frequent in tumors and cell lines. Of special interest was the fact that a group of cell lines that became more aggressive after animal passaging expressed more cyclins D2 and D3 than their respective parental lines did. In addition, SCCs had higher cyclin D3 expression levels than papillomas, and metastases had higher levels than the respective primary tumors, indicating that overexpression of cyclin D3 may be associated with increased aggressiveness of mouse SCC. Interestingly, overexpression of cyclin E was seen in most SCCs induced by a complete carcinogenesis protocol with benzo[a]pyrene (B(a)P) and only in a few SCCs induced by a two-stage carcinogenesis protocol using 7,12-dimethylbenz[a]anthracene as initiator. In contrast, more of the latter tumors overexpressed cyclin D1 and D2 than those induced by B(a)P. Thus, it is possible that different components of the cell-cycle machinery are involved in proliferative dysfunctions that take place during tumor development with different carcinogenesis protocols. Taken together, these results indicate that overexpression of G1 cyclins and their related Cdks is a significant molecular abnormality that could be involved in the process of tumor progression.
Zhang
S Y
SY
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Liu
S C
SC
Goodrow
T
T
Morris
R
R
Klein-Szanto
A J
AJ
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001564:Benzo(a)pyrene; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D019938:Cyclin D1; D056742:Cyclin D2; D056743:Cyclin D3; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis*; D016213:Cyclins / Q000096:biosynthesis*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D051379:Mice; D015513:Oncogene Proteins / Q000096:biosynthesis; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016196:S Phase; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D015513:Oncogene Proteins; D019938:Cyclin D1; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D018844:Cyclin-Dependent Kinases; D013755:Tetradecanoylphorbol Acetate