Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells.
To determine the mechanism by which differentiation-inducing factor-1 (DIF-1), a morphogen of Dictyostelium discoideum, inhibits tumor cell proliferation, we examined the effect of DIF-1 on the gene expression of cyclin D1. DIF-1 strongly reduced the expression of cyclin D1 mRNA and correspondingly decreased the amount of beta-catenin in HeLa cells and squamous cell carcinoma cells. DIF-1 activated glycogen synthase kinase-3beta (GSK-3beta) and inhibition of GSK-3beta attenuated the DIF-1-induced beta-catenin degradation, indicating the involvement of GSK-3beta in this effect. Moreover, DIF-1 reduced the activities of T-cell factor (TCF)/lymphoid enhancer factor (LEF) reporter plasmid and a reporter gene driven by the human cyclin D1 promoter. Eliminating the TCF/LEF consensus site from the cyclin D1 promoter diminished the effect of DIF-1. These results suggest that DIF-1 inhibits Wnt/beta-catenin signaling, resulting in the suppression of cyclin D1 promoter activity.
Yasmin
Tania
T
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Takahashi-Yanaga
Fumi
F
Mori
Jun
J
Miwa
Yoshikazu
Y
Hirata
Masato
M
Watanabe
Yutaka
Y
Morimoto
Sachio
S
Sasaguri
Toshiyuki
T
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006367:HeLa Cells; D006588:Hexanones / Q000008:administration & dosage*; D006801:Humans
D006588:Hexanones; C053433:1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone; D019938:Cyclin D1