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Carcinogenesis Advance Access originally published online on March 26, 2007
Carcinogenesis 2007 28(9):2028-2035; doi:10.1093/carcin/bgm066
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Haploinsufficiency of the cdc2l gene contributes to skin cancer development in mice

Anupama Chandramouli{dagger}, Jiaqi Shi{dagger}, Yongmei Feng, Hana Holubec1, Renée M.Shanas, Achyut K. Bhattacharyya, Wenxin Zheng and Mark A. Nelson*

Department of Pathology, Arizona Cancer Center, University of Arizona, 1501 North Campbell Avenue, LSN 550, Tucson, AZ, USA
1 Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ, USA

* To whom correspondence should be addressed. Tel: +520 626 2619; Fax: +520 626 8864; Email: mnelson{at}azcc.arizona.edu

The Cdc2L gene encodes for the cyclin-dependent kinase 11 (CDK11) protein. Loss of one allele of Cdc2L and reduced CDK11 expression has been observed in several cancers, implicating its association with carcinogenesis. To directly investigate the role of CDK11 in carcinogenesis, we first generated cdc2l haploinsufficient mice by gene trap technology and then studied the susceptibility of these gene-trapped (cdc2lGT) mice to chemical-mediated skin carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis model. Wild-type and cdc2lGT mice were subjected to a single topical application of initiation by DMBA and promotion twice a week for 19 weeks with TPA. At 19 weeks, 70% of the cdc2lGT mice and 60% of the cdc2l+/+ mice developed benign papillomas. However, there was an overall 3-fold increase in the average number of tumors per mouse observed in cdc2lGT mice as compared with cdc2l+/+ mice. There was also an increased frequency of larger papillomas in cdc2lGT mice. By using the polymerase chain reaction–restriction fragment length polymorphism assay, we found A to T transversion mutations at the 61st codon of H-ras gene in the papilloma tissue of both cdc2lGT mice and cdc2l+/+ mice. Ki-67 staining revealed increased proliferation in the papillomas of cdc2lGT (77.75%) as compared with cdc2l+/+ (30.84%) tumors. These studies are the first to show that loss of one allele of cdc2l gene, encoding CDK11, facilitates DMBA/TPA-induced skin carcinogenesis in vivo.

Abbreviations: DMBA, 7,12-dimethylbenz[a]anthracene; ES, embryonic stem; PCR, polymerase chain reaction; PI, proliferative index; RT, reverse transcription; TPA, 12-O-tetradecanoylphorbol-13-acetate

{dagger} These authors contributed equally to this study.

Received January 16, 2007; revised March 2, 2007; accepted March 13, 2007.


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