Cyclin-dependent kinase inhibitor p27(Kip1) is required for mouse mammary gland morphogenesis and function.
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 p27 on cyclin D1-Cdk4 complexes suggests that p27 deficiency might recapitulate the hypoplastic mammary phenotype of cyclin D1-deficient animals. These hypotheses were investigated in postnatal p27-deficient (p27(-/-)), hemizygous (p27(+/)-), or wild-type (p27(+/+)) mammary glands. Mammary glands from p27(+/)- mice displayed increased ductal branching and proliferation with delayed postlactational involution. In contrast, p27(-/-) mammary glands or wild-type mammary fat pads reconstituted with p27(-/-) epithelium produced the opposite phenotype: hypoplasia, low proliferation, decreased ductal branching, impaired lobuloalveolar differentiation, and inability to lactate. The association of cyclin D1 with Cdk4, the kinase activity of Cdk4 against pRb in vitro, the nuclear localization of cyclin D1, and the stability of cyclin D1 were all severely impaired in p27(-/-) mammary epithelial cells compared with p27(+/+) and p27(+/-) mammary epithelial cells. Therefore, p27 is required for mammary gland development in a dose-dependent fashion and positively regulates cyclin D-Cdk4 function in the mammary gland.
Muraoka
R S
RS
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Lenferink
A E
AE
Simpson
J
J
Brantley
D M
DM
Roebuck
L R
LR
Yakes
F M
FM
Arteaga
C L
CL
D021581:Active Transport, Cell Nucleus; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D007774:Lactation; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis; D009924:Organ Culture Techniques; D010641:Phenotype; D011247:Pregnancy; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases