Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis

D. I. Lin, M. D. Lessie, A. B. Gladden, C. H. Bassing, K. U. Wagner, J. A. Diehl

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Abstract

Cyclin D1 levels are maintained at steady state by phosphorylation- dependent nuclear export and polyubiquitination by SCF FBX4-αB crystallin. Inhibition of cyclin D1 proteolysis has been implicated as a causative factor leading to its overexpression in breast and esophageal carcinomas; however, the contribution of stable cyclin D1 to the genesis of such carcinomas has not been evaluated. We therefore generated transgenic mice wherein expression of either wild-type or a stable cyclin D1 allele (D1T286A) is regulated by MMTV-LTR. MMTV-D1T286A mice developed mammary adenocarcinomas at an increased rate relative to MMTV-D1 mice. Similar to human cancers that overexpress cyclin D1, D1T286A tumors were estrogen receptor-positive and exhibited estrogen-dependent growth. Collectively, these results suggest that temporal control of cyclin D1 subcellular localization and proteolysis is critical for maintenance of homeostasis within the mammary epithelium.

Original languageEnglish (US)
Pages (from-to)1231-1242
Number of pages12
JournalOncogene
Volume27
Issue number9
DOIs
StatePublished - Feb 21 2008

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Keywords

  • CDK4
  • Cyclin D1
  • FBX4
  • Mammary gland
  • PD0332991

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Lin, D. I., Lessie, M. D., Gladden, A. B., Bassing, C. H., Wagner, K. U., & Diehl, J. A. (2008). Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis. Oncogene, 27(9), 1231-1242. https://doi.org/10.1038/sj.onc.1210738