Abstract
In a previous study, we reported that overexpression of cyclin-dependent kinase-4 (CDK4) in mouse epidermis results in epidermal hyperplasia, hypertrophy and severe dermal fibrosis. In this study, we have investigated the susceptibility to skin tumor formation by forced expression of CDK4. Skin tumors from transgenic mice showed a dramatic increase in the rate of malignant progression to squamous cell carcinomas (SCC) in an initiation-promotion protocol. Histopathological analysis of papillomas from transgenic mice showed an elevated number of premalignant lesions characterized by dysplasia and marked atypia. Interestingly, transgenic mice also developed tumors in initiated but not promoted skin, demonstrating that CDK4 replaced the action of tumor promoters. These results suggest that expression of cyclin D1 upon ras activation synergizes with CDK4 overexpression. However, cyclin D1 transgenic mice and double transgenic mice for cyclin D1 and CDK4 did not show increased malignant progression in comparison to CDK4 transgenic mice. Biochemical analysis of tumors showed that CDK4 sequesters the CDK2 inhibitors p27Kip1 and p21Cip1, suggesting that indirect activation of CDK2 plays an important role in tumor development. These results indicate that, contrary to the general assumption, the catalytic subunit, CDK4, has higher oncogenic activity than cyclin D1, revealing a potential use of CDK4 as therapeutic target.
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Abbreviations
- CDKs:
-
cyclin-dependent kinases
- CKI:
-
cyclin-dependent kinases inhibitor
- DMBA:
-
7,12-dimethylbenz[a]anthracene
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
- IP:
-
immunoprecipitation
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Acknowledgements
We especially thank Dr Dennis Johnston for assistance with the statistical analysis, Dr Susan Fischer for helpful reading and discussion of this paper, April Weiss for helping with the mouse experiments, Cassie Bigbee for technical support, the Science Park animal facility personnel and the Science Park histology service for assistance with the immunohistochemical staining. This study is supported by NIH Grants CA 42157, CA 57596 and CA 90864, Cancer Center Grant CA 16672 to MDACC for the animal facility, Funds from the University Cancer Foundation at the University of Texas M. D. Anderson Cancer Center and NIEHS Center Grant ES07784.
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Miliani de Marval, P., Macias, E., Conti, C. et al. Enhanced malignant tumorigenesis in Cdk4 transgenic mice. Oncogene 23, 1863–1873 (2004). https://doi.org/10.1038/sj.onc.1207309
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DOI: https://doi.org/10.1038/sj.onc.1207309
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