The cyclin-dependent kinase inhibitor p27 (Kip1) regulates both DNA synthesis and apoptosis in mammary epithelium but is not required for its functional development during pregnancy

被引:20
作者
Davison, EA
Lee, CSL
Naylor, MJ
Oakes, SR
Sutherland, RL
Hennighausen, L
Ormandy, CJ
Musgrove, EA
机构
[1] St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, Sydney, NSW 2010, Australia
[2] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1210/me.2003-0199
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Decreased expression of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) is common in breast cancer and is associated with poor prognosis. p27 is also an important mediator of steroidal regulation of cell cycle progression. We have therefore investigated the role of p27 in mammary epithelial cell proliferation. Examination of the two major functions of p27, assembly of cyclin D1-Cdk4 complexes and inhibition of Cdk2 activity, revealed that cyclin D1-Cdk4 complex formation was not impaired in p27(-/-) mammary epithelial cells in primary culture. However, cyclin E-Cdk2 activity was increased approximately 3-fold, indicating that the CDK inhibitory function of p27 is important in mammary epithelial cells. Increased epithelial DNA synthesis was observed during pregnancy in p27(-/-) mammary gland transplants, but this was paralleled by increased apoptosis. During pregnancy and at parturition, development and differentiation of p27(+/+) and p27(-/-) mammary tissue were indistinguishable. These results demonstrate a role for p27 in both the proliferation and survival of mammary epithelial cells. However, the absence of morphological and cellular defects in p27(-/-) mammary tissue during pregnancy raises the possibility that loss of p27 in breast cancer may not confer an overall growth advantage unless apoptosis is also impaired.
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收藏
页码:2436 / 2447
页数:12
相关论文
共 47 条
[1]  
BRADBURY JM, 1995, DEV BIOL, V170, P5535
[2]   Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells [J].
Cariou, S ;
Donovan, JCH ;
Flanagan, WM ;
Milic, A ;
Bhattacharya, N ;
Slingerland, JM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (16) :9042-9046
[3]   A pure estrogen antagonist inhibits cyclin E-Cdk2 activity in MCF-7 breast cancer cells and induces accumulation of p130-E2F4 complexes characteristic of quiescence [J].
Carroll, JS ;
Prall, OWJ ;
Musgrove, EA ;
Sutherland, RL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (49) :38221-38229
[4]  
Chen TT, 1999, MAR BIOTECHNOL, V1, P1
[5]   The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts [J].
Cheng, MG ;
Olivier, P ;
Diehl, JA ;
Fero, M ;
Roussel, MF ;
Roberts, JM ;
Sherr, CJ .
EMBO JOURNAL, 1999, 18 (06) :1571-1583
[6]  
Chiarle R, 2001, BREAST CANCER RES, V3, P91
[7]   Altered p27Kip1 phosphorylation, localization, and function in human epithelial cells resistant to transforming growth factor β-mediated G1 arrest [J].
Ciarallo, S ;
Subramaniam, V ;
Hung, W ;
Lee, JH ;
Kotchetkov, R ;
Sandhu, C ;
Milic, A ;
Slingerland, JM .
MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (09) :2993-3002
[8]   A new pathway for mitogen-dependent Cdk2 regulation uncovered in p27Kip1-deficient cells [J].
Coats, S ;
Whyte, P ;
Fero, ML ;
Lacy, S ;
Chung, G ;
Randel, E ;
Firpo, E ;
Roberts, JM .
CURRENT BIOLOGY, 1999, 9 (04) :163-173
[9]   p27/kip I expression in normal epithelium, benign and neoplastic breast lesions [J].
De Paola, F ;
Vecci, AM ;
Granato, AM ;
Liverani, M ;
Monti, F ;
Innoceta, AM ;
Gianni, L ;
Saragoni, L ;
Ricci, M ;
Falcini, F ;
Amadori, D ;
Volpi, A .
JOURNAL OF PATHOLOGY, 2002, 196 (01) :26-31
[10]   The role of apoptosis in creating and maintaining luminal space with normal and oncogene-expressing mammary acini [J].
Debnath, J ;
Mills, KR ;
Collins, NL ;
Reginato, MJ ;
Muthuswamy, SK ;
Brugge, JS .
CELL, 2002, 111 (01) :29-40