Document Detail

Regulation of cyclin D1 and p16(INK4A) is critical for growth arrest during mammary involution.
MedLine Citation:
PMID:  11751403     Owner:  NLM     Status:  MEDLINE    
A coordinated growth arrest during mammary involution completes the dramatic changes in mammary cell proliferation seen during pregnancy and lactation. Signals regulating this arrest are poorly understood, despite their potential relevance to oncogenesis. Here we report that the arrest involves a unique pulse of p16(INK4A) expression in vivo, which accompanies decreased cyclin D1 expression and a shift to an active repressor E2F4 complex. We used INK4A/ARF-/- mice as well as cyclin D1 and p16(INK4A) transgenic strains to examine the physiological significance of these patterns. p16(INK4A) directly regulated the in vivo transition from E2F3 to E2F4 as the major E2F DNA binding activity, and its contribution to growth arrest was independent of cyclin D1. Transgenic cyclin D1 expression prevented normal terminal differentiation by ablating the p16(INK4A) pulse, abolishing the shift from E2F3 to E2F4, derepressing E2F target genes, and expanding a stem cell population. The effects of cyclin D1 were reversed by restoring p16(INK4A) but were not seen in INK4A/ARF-/- mice. Our results indicate that cyclin D1 may contribute to tumorigenesis by altering cell differentiation and demonstrate a significant function for p16(INK4A) in development in vivo. These regulatory mechanisms used during mammary involution offer a potential explanation for the protective effect of pregnancy against breast cancer.
M Gadd; C Pisc; J Branda; V Ionescu-Tiba; Z Nikolic; C Yang; T Wang; G M Shackleford; R D Cardiff; E V Schmidt
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  61     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2001 Dec 
Date Detail:
Created Date:  2001-12-25     Completed Date:  2002-01-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8811-9     Citation Subset:  IM    
Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
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MeSH Terms
3T3 Cells
Cell Differentiation / genetics
Cell Division / physiology
Cyclin D1 / biosynthesis,  genetics,  physiology*
Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis,  genetics,  physiology*
Gene Expression Regulation, Developmental
Genetic Vectors / genetics
Lactation / metabolism,  physiology
Mammary Glands, Animal / growth & development*,  physiology
Mammary Tumor Virus, Mouse / genetics
Mice, Transgenic
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p16; 136601-57-5/Cyclin D1

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