Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution.
In order to elucidate the mechanisms by which estrogens and antiestrogens modulate the growth of breast cancer cells, we have characterized the changes induced by estradiol that occur during the G1 phase of the cell cycle of MCF-7 human mammary carcinoma cells. Addition of estradiol relieves the cell cycle block created by tamoxifen treatment, leading to marked activation of cyclin E-cdk2 complexes and phosphorylation of the retinoblastoma protein within 6 h. Cyclin D1 levels increase significantly while the levels of cyclin E, cdk2, and the p21 and p27 cdk inhibitors are relatively constant. However, the p21 cdk inhibitor shifts from its association with cyclin E-cdk2 to cyclin D1-cdk4, providing an explanation for the observed activation of the cyclin E-cdk2 complexes. These results support the notion that cyclin D1 has an important role in steroid-dependent cell proliferation and that estrogen, by regulating the activities of G1 cyclin-dependent kinases, can control the proliferation of breast cancer cells.
Planas-Silva
M D
MD
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Weinberg
R A
RA
D001943:Breast Neoplasms / Q000473:pathology*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism* / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000502:physiology; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D015513:Oncogene Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004958:Estradiol; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases