TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

• Published in: Oncogene Vol. 16; no. 26; pp. 3445 - 3454
• Main Authors: KO, T. C, WANGSHENG YU, SAKAI, T, HONGMIAO SHENG, JINYI SHAO, BEAUCHAMP, R. D, THOMPSON, E. A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 02.07.1998; Nature Publishing Group
• Subjects: Antisense oligonucleotides; Biological and medical sciences; Cancer; Cell cycle; Cell cycle, cell proliferation; Cell growth; Cell physiology; Cell proliferation; Cyclin D1; Cyclin-dependent kinase 4; D1 protein; DNA biosynthesis; Epithelial cells; Fundamental and applied biological sciences. Psychology; G1 phase; Intestine; Kinases; Molecular and cellular biology; Phosphorylation; Retina; Retinoblastoma; Retinoblastoma protein; S phase; Transforming growth factor-b1; Cell proliferation; Rat; Rodentia; Gut; Gene expression; Cyclin D1; Vertebrata; G1 Phase; Regulation(control); Mammalia; Cell line; Shutdown; Gene; Cell cycle; Epithelial cell; Transforming growth factor β1
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201902

Transforming growth factor-beta 1 (TGF-β1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-β1-mediated cell cycle arrest. TGF-β1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGF-β1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no effect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-β1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-β1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-β1-mediated arrest of intestinal epithelial cell proliferation.