Cyclin-dependent Kinase Inhibitor p27Kip1 Is Required for Mouse Mammary Gland Morphogenesis and Function

doi:10.1083/jcb.153.5.917

Published online 21 May 2001. doi:10.1083/jcb.153.5.917

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© The Rockefeller University Press, 0021-9525/2001/5/917/ $5.00
The Journal of Cell Biology, Volume 153, Number 5, May 28, 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

Correspondence to: Carlos L. Arteaga, Div. of Oncology, Vanderbilt University School of Medicine, 22nd Ave. S., 1956 TVC, Nashville, TN 37232-5536. Tel:(615) 936-3524 Fax:(615) 936-1790 E-mail: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^+/-), orwild-type (p27^+/+) mammary glands. Mammary glands from p27^+/-mice displayed increased ductal branching and proliferationwith delayed postlactational involution. In contrast, p27^-/-mammary glands or wild-type mammary fat pads reconstituted withp27^-/- epithelium produced the opposite phenotype: hypoplasia,low proliferation, decreased ductal branching, impaired lobuloalveolardifferentiation, and inability to lactate. The association ofcyclin D1 with Cdk4, the kinase activity of Cdk4 against pRbin vitro, the nuclear localization of cyclin D1, and the stabilityof cyclin D1 were all severely impaired in p27^-/- mammary epithelialcells compared with p27^+/+ and p27^+/- mammary epithelial cells.Therefore, p27 is required for mammary gland development ina dose-dependent fashion and positively regulates cyclin D–Cdk4function in the mammary gland.

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

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