Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis.
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.
Lin
D I
DI
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lessie
M D
MD
Gladden
A B
AB
Bassing
C H
CH
Wagner
K U
KU
Diehl
J A
JA
D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000821:virology; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D005260:Female; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D006868:Hydrolysis; D015674:Mammary Neoplasms, Animal / Q000209:etiology* / Q000378:metabolism* / Q000821:virology; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000472:pathogenicity; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D013347:Subcellular Fractions / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
D019938:Cyclin D1