Transforming growth factor-beta 1 stimulates or inhibits cell growth via down- or up-regulation of p21/Waf1.
Transforming growth factor-beta (TGF-beta) regulates cell proliferation positively or negatively. The mitoinhibition by TGF-beta has been attributed to induction of cyclin-dependent kinase (CDK) inhibitors, such as p15/ Ink4B, p27/Kip1, and p21/Waf1 also known as Cip1 and Sdi1. However, the biological process by which TGF-beta exerts the stimulatory effects on cell growth remains poorly understood. Here we report that TGF-beta 1 stimulates DNA synthesis of IMR-90 human embryonic lung fibroblasts but inhibits that of HuCCT1 human cholangiocarcinoma cells, via down- or up-regulation of p21/Waf1, respectively. TGF-beta 1 markedly suppresses IMR-90 cells to express two different kinds of the p21/Waf1 gene transcription factors, the p53 tumor suppressor and the interferon regulatory factor-1 (IRF-1). This is followed by a marked decrease in expression of p21/Waf1 in a manner consistent with the timing of activation of cyclin E-associated kinase, which normally accompanies the G1-S transition in the cell cycle. Contrarily, TGF-beta 1-induced inhibition of DNA synthesis in HuCCT1 cells is preceded by IRF-1-dependent but p53-independent up-regulation of p21/Waf1 expression followed by inactivation of cyclin E-associated kinase. Thus the cell growth stimulation or inhibition by TGF-beta 1 are mediated by the down- or up-regulation of p21/ Waf1, respectively.
Miyazaki
M
M
Department of Cell Biology, Okayama University Medical School, Japan. hiromiya@med.okayama-u.ac.jp
Ohashi
R
R
Tsuji
T
T
Mihara
K
K
Gohda
E
E
Namba
M
M
D042846:CDC2-CDC28 Kinases; D002455:Cell Division; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D008168:Lung / Q000166:cytology / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases