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Oncogene. 2008 Feb 21;27(9):1231-42. Epub 2007 Aug 27.

Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis.

Author information

1
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

Cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and polyubiquitination by SCF(FBX4-alphaB 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.

PMID:
17724472
PMCID:
PMC3733559
DOI:
10.1038/sj.onc.1210738
[Indexed for MEDLINE]
Free PMC Article

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