Effects of TGF-beta 1 (transforming growth factor-beta 1) on the cell cycle regulation of human breast adenocarcinoma (MCF-7) cells.
The antiproliferative effects of TGF-beta 1 were investigated in a human breast adenocarcinoma cell line (MCF-7). We report that TGF-beta 1 inhibits proliferation through cell cycle arrest in G1. A MCF-7 cell subline (MCF-7(-)), in which the type II TGF-beta receptor is not detected, was shown to be resistant to TGF-beta 1 growth inhibitory effect. Cdk2 kinase activity was inhibited in the MCF-7 sensitive cell subline in parallel with the inhibition of cell cycle progression. In both sensitive and resistant cell lines, TGF-beta 1 treatment did not affect cdk2, cdk4, cyclin E and cyclin D1 mRNA and protein levels. However, in the MCF-7 sensitive cell subline, a time-dependent increase in cells positive for p21WAF1/CIP1 nuclear localization was observed after TGF-beta 1 treatment. These findings suggest that TGF-beta 1 inhibition of MCF-7 cell proliferation is achieved through a type II receptor-dependent down-regulation of Cdk2 kinase activity without modification of Cdk and cyclin expression, but correlated with an increase in p21WAF1/CIP1 nuclear accumulation.
Mazars
P
P
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Toulouse, France.
Barboule
N
N
Baldin
V
V
Vidal
S
S
Ducommun
B
B
Valette
A
A
D000230:Adenocarcinoma; D001943:Breast Neoplasms; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000737:chemistry; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D016193:G1 Phase / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II