Impaired nuclear export of tumor-derived c-terminal truncated cyclin D1 mutant in ESCC cancer

Hao,Meili; Chen,Xiangmei; Zhang,Ting; Shen,Tao; Xie,Qing; Xing,Xiujuan; Gu,Hongxi; Lu,Fengmin

doi:10.3892/ol.2011.404

Impaired nuclear export of tumor-derived c-terminal truncated cyclin D1 mutant in ESCC cancer

Authors:
- Meili Hao
- Xiangmei Chen
- Ting Zhang
- Tao Shen
- Qing Xie
- Xiujuan Xing
- Hongxi Gu
- Fengmin Lu
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Affiliations: Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Microbiology and Infectious Disease Center, Peking University Health Science Center, Beijing 100191, P.R. China
Published online on: September 2, 2011 https://doi.org/10.3892/ol.2011.404
Pages: 1203-1211

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Abstract

Cyclin D1 is a significant regulator of the G1- to S-phase transition and is often aberrant in human tumors of various origins. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms by which they contribute to neoplasia remaind to be elucidated. We previously identified a cyclin D1 mutation (Δ266-295) in esophageal cancer with deleted codons from 266 to 295 of wild-type cyclin D1, the critical COOH-terminal regulatory sequences necessary for cyclin D1 nuclear export. In the present study, this cancer-derived cyclin D1-Δ266-295 was shown to be a constitutively nuclear cyclin D1 protein with a significantly increased oncogenic potential. Moreover, the cancer-derived cyclin D1-Δ266-295 mutant was found to retain its ability to bind to and activate CDK4, which in turn phosphorylates and inactivates the pRb protein and promotes cell cycle progression. In comparison to wild-type cyclin D1a, D1-Δ266-295 exhibited enforced nuclear accumulation. In addition, the transient transfection and ectopic expression of this nuclear localized D1-Δ266-295 up-regulated endogenous Notch1 expression, indicating that the mutant retained its ability as a transcriptional regulator. Furthermore, data from the flow cytometry assay showed that D1-Δ266-295 fractionally increased >4N cell accumulation, and further analysis suggested the retriggering of DNA replication relevant to its inhibition of Cdt1 proteolysis. Therefore, the inappropriate nuclear localization of this cyclin D1 mutant may interfere with DNA replication in cultured cells, thereby contributing to genomic instability.

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