Cyclin-Dependent Kinase Inhibitor P27Kip1 Is Required for Mouse Mammary Gland Morphogenesis and Function

doi:10.1083/jcb.153.5.917

Published online 28 May 2001. doi:10.1083/jcb.153.5.917

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© The Rockefeller University Press, 0021-9525/2001//917 $5.00
The Journal of Cell Biology, Volume 153, Number 5, , 2001 917-932

Original Article

Cyclin-Dependent Kinase Inhibitor P27^Kip1 Is Required for Mouse Mammary Gland Morphogenesis and Function

Rebecca S. Muraoka^a, Anne E.G. Lenferink^c, Jean Simpson^b^,e, Dana M. Brantley^c, L. Renee Roebuck^c, F. Michael Yakes^c, and Carlos L. Arteaga^a^,c^,d^,e

^a Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
^b Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
^c Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
^d Department of Veteran Affairs Medical Center, Nashville, Tennessee 37232
^e Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232
Div. of Oncology, Vanderbilt University School of Medicine, 22nd Ave. S., 1956 TVC, Nashville, TN 37232-5536.(615) 936-1790(615) 936-3524

carlos.arteaga{at}mcmail.vanderbilt.edu

We have studied the role of the cyclin-dependent kinase (Cdk)inhibitor p27^Kip1 in postnatal mammary gland morphogenesis.Based on its ability to negatively regulate cyclin/Cdk function,loss of p27 may result in unrestrained cellular proliferation.However, recent evidence about the stabilizing effect of p27on cyclin D1–Cdk4 complexes suggests that p27 deficiencymight recapitulate the hypoplastic mammary phenotype of cyclinD1–deficient animals. These hypotheses were investigatedin postnatal p27-deficient (p27^–/–), hemizygous(p27^+/–), or wild-type (p27^+/+) mammary glands. Mammaryglands from p27^+/– mice displayed increased ductal branchingand proliferation with delayed postlactational involution. Incontrast, p27^–/– mammary glands or wild-type mammaryfat pads reconstituted with p27^–/– epithelium producedthe opposite phenotype: hypoplasia, low proliferation, decreasedductal branching, impaired lobuloalveolar differentiation, andinability to lactate. The association of cyclin D1 with Cdk4,the kinase activity of Cdk4 against pRb in vitro, the nuclearlocalization of cyclin D1, and the stability of cyclin D1 wereall severely impaired in p27^–/– mammary epithelialcells compared with p27^+/+ and p27^+/– mammary epithelialcells. Therefore, p27 is required for mammary gland developmentin a dose-dependent fashion and positively regulates cyclinD–Cdk4 function in the mammary gland.

Key Words: p27 • mammary gland • cyclin D1 • growth • apoptosis

A.E.G. Lenferink's present address is Biotechnology ResearchInstitute, National Research Council, Montreal, PQ, Canada H4P2R2.

Abbreviations used in this paper: Cdk, cyclin-dependent kinase;CKI, Cdk inhibitor; dpc, days postcoitum; dpfw, days postforcedwean; HH1, histone H1; IP, immunoprecipitation; PMEC, primarymammary epithelial cell; Stat, signal transducer and activatorof transcription; TEB, terminal end bud; TUNEL, terminal deoxynucleotidyltransferase–mediated dUTP–biotin nick end labeling.

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