Journal
ONCOGENE
Volume 27, Issue 9, Pages 1231-1242Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210738
Keywords
CDK4; cyclin D1; FBX4; mammary gland; PD0332991
Funding
- NCI NIH HHS [CA11360, R01 CA125195-01A1, R01 CA111360-05, R01 CA111360, R01 CA125195] Funding Source: Medline
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Cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and polyubiquitination by SCFFBX4-alpha B (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.
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