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Aberrant cell cycle progression contributes to the early-stage accelerated carcinogenesis in transgenic epidermis expressing the dominant negative TGFβRII

Oncogene volume 19, pages 3623–3631 (2000)Cite this article

Abstract

Mutations in the transforming growth factor β type II receptor (TGFβRII) have been found in various malignant tumors, suggesting that loss of TGFβ signaling plays a causal role in late-stage cancer development. To test whether loss of TGFβRII is involved in early-stage carcinogenesis, we have generated transgenic mice expressing a dominant negative TGFβRII (ΔβRII) in the epidermis. These mice exhibited an increased susceptibility to chemical carcinogenesis protocols at both early and late stages. In the current study, parameters for cell cycle progression and chromosome instability were analysed in ΔβRII tumors. ΔβRII papillomas showed an increased S phase in flow cytometry. Bromodeoxyuridine (BrdU) labeling and mitotic indices in ΔβRII papillomas also showed a threefold increase compared to papillomas developing in non-transgenic mice. When papillomas further progressed to squamous cell carcinomas (SCC), both control and ΔβRII SCC showed similar BrdU labeling indices and percentages of S phase cells. However, ΔβRII SCC cells showed a sixfold increase in the G2/M population. Mitotic indices in ΔβRII SCC also showed a threefold increase compared to non-transgenic SCC. Consistent with a perturbed cell cycle, ΔβRII papillomas and SCC showed reduced expression of the TGFβ target genes p15 (INK4b), p21 (WAF-1) and p27 (Kip1), inhibitors of cyclin-dependent kinases (cdks). However, most ΔβRII papilloma cells exhibited normal centrosome numbers, and ΔβRII SCC exhibited a similar extent of centrosome abnormalities compared to control SCC (35–40% cells). Most of ΔβRII SCC exhibited diploid chromosome profiles. These data indicate that inactivation of TGFβRII accelerates skin tumorigenesis at early stages by the acceleration of loss of cell cycle control, but not by increased chromosome instability.

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Acknowledgements

The authors would like to give special thanks to Dr Dennis R Roop for his critical comments on the manuscript. We would also like to thank Dr Charles J Sherr (St Jude Children Hospital, Memphis, TN, USA) for providing mouse p15 and p16 cDNA clones, and Dr Ron Balczon (University of South Alabama, Mobile, AL, USA) for providing human antiserum for PCM-1. Mrs Mattie Brooks provided excellent technical assistance. This work was supported by a Career Development Award from the Dermatology Foundation and NIH grant CA79998 to X-J Wang and NIH grant CA64255 to BR Brinkley.

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Authors and Affiliations

  1. Department of Otolaryngology, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Cindy Go

  2. Department of Dermatology, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Wei He & Xiao-Jing Wang

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Ling Zhong, Ping Li, Juan Huang, Bill R Brinkley & Xiao-Jing Wang

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  1. Cindy Go
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Go, C., He, W., Zhong, L. et al. Aberrant cell cycle progression contributes to the early-stage accelerated carcinogenesis in transgenic epidermis expressing the dominant negative TGFβRII. Oncogene 19, 3623–3631 (2000). https://doi.org/10.1038/sj.onc.1203701

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