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Title: Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells

Abstract

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-3{beta} (GSK-3{beta}) and inhibition of GSK-3{beta} attenuated the DIF-1-induced {beta}-catenin degradation, indicating the involvement of GSK-3{beta} 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.

Authors:
 [1];  [2];  [1];  [1];  [3];  [4];  [1];  [1]
  1. Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 (Japan)
  2. Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 (Japan). E-mail: yanaga@clipharm.med.kyushu-u.ac.jp
  3. Department of Molecular and Cellular Biochemistry, Graduate School of Dental Sciences, Kyushu University, Fukuoka 812-8582 (Japan)
  4. Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577 (Japan)
Publication Date:
OSTI Identifier:
20793218
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 338; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2005.10.018; PII: S0006-291X(05)02264-3; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOMAS; CELL PROLIFERATION; GENES; GLYCOGEN; HELA CELLS; INHIBITION; PROMOTERS

Citation Formats

Yasmin, Tania, Takahashi-Yanaga, Fumi, Mori, Jun, Miwa, Yoshikazu, Hirata, Masato, Watanabe, Yutaka, Morimoto, Sachio, and Sasaguri, Toshiyuki. Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells. United States: N. p., 2005. Web. doi:10.1016/J.BBRC.2005.1.
Yasmin, Tania, Takahashi-Yanaga, Fumi, Mori, Jun, Miwa, Yoshikazu, Hirata, Masato, Watanabe, Yutaka, Morimoto, Sachio, & Sasaguri, Toshiyuki. Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells. United States. doi:10.1016/J.BBRC.2005.1.
Yasmin, Tania, Takahashi-Yanaga, Fumi, Mori, Jun, Miwa, Yoshikazu, Hirata, Masato, Watanabe, Yutaka, Morimoto, Sachio, and Sasaguri, Toshiyuki. Fri . "Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells". United States. doi:10.1016/J.BBRC.2005.1.
@article{osti_20793218,
title = {Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells},
author = {Yasmin, Tania and Takahashi-Yanaga, Fumi and Mori, Jun and Miwa, Yoshikazu and Hirata, Masato and Watanabe, Yutaka and Morimoto, Sachio and Sasaguri, Toshiyuki},
abstractNote = {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-3{beta} (GSK-3{beta}) and inhibition of GSK-3{beta} attenuated the DIF-1-induced {beta}-catenin degradation, indicating the involvement of GSK-3{beta} 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.},
doi = {10.1016/J.BBRC.2005.1},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 338,
place = {United States},
year = {Fri Dec 16 00:00:00 EST 2005},
month = {Fri Dec 16 00:00:00 EST 2005}
}
  • Differentiation-inducing factors (DIFs) are morphogens which induce cell differentiation in Dictyostelium. We reported that DIF-1 and DIF-3 inhibit proliferation and induce differentiation in mammalian cells. In this study, we investigated the effect of DIF-1 on oral squamous cell carcinoma cell lines NA and SAS, well differentiated and poorly differentiated cell lines, respectively. Although DIF-1 did not induce the expression of cell differentiation makers in these cell lines, it inhibited the proliferation of NA and SAS in a dose-dependent manner by restricting the cell cycle in the G{sub 0}/G{sub 1} phase. DIF-1 induced cyclin D1 degradation, but this effect was preventedmore » by treatment with lithium chloride and SB216763, the inhibitors of glycogen synthase kinase-3{beta} (GSK-3{beta}). Depletion of endogenous GSK-3{beta} by RNA interference also attenuated the effect of DIF-1 on cyclin D1 degradation. Therefore, we investigated the effect of DIF-1 on GSK-3{beta} and found that DIF-1 dephosphorylated GSK-3{beta} on Ser{sup 9} and induced the nuclear translocation of GSK-3{beta}, suggesting that DIF-1 activated GSK-3{beta}. Then, we examined the effect of DIF-1 on cyclin D1 mutants (Thr286Ala, Thr288Ala, and Thr286/288Ala). We revealed that Thr286Ala and Thr286/288Ala mutants were highly resistant to DIF-1-induced degradation compared with wild-type cyclin D1, indicating that the phosphorylation of Thr{sup 286} was critical for cyclin D1 degradation induced by DIF-1. These results suggest that DIF-1 induces degradation of cyclin D1 through the GSK-3{beta}-mediated phosphorylation of Thr{sup 286}.« less
  • Arsenic is a well-documented human carcinogen associated with skin carcinogenesis. Our previous work reveals that arsenite exposure is able to induce cell transformation in mouse epidermal cell JB6 Cl41 through the activation of ERK, rather than JNK pathway. Our current studies further evaluate downstream pathway in low dose arsenite-induced cell transformation in JB6 Cl41 cells. Our results showed that treatment of cells with low dose arsenite induced activation of c-Jun/AP-1 pathway, and ectopic expression of dominant negative mutant of c-Jun (TAM67) blocked arsenite-induced transformation. Furthermore, our data indicated that cyclin D1 was an important downstream molecule involved in c-Jun/AP-1-mediated cellmore » transformation upon low dose arsenite exposure, because inhibition of cyclin D1 expression by its specific siRNA in the JB6 Cl41 cells resulted in impairment of anchorage-independent growth of cells induced by low dose arsenite. Collectively, our results demonstrate that c-Jun/AP-1-mediated cyclin D1 expression is at least one of the key events implicated in cell transformation upon low dose arsenite exposure.« less
  • The regulator of cell cycle progression, cyclin D1, is up-regulated in breast cancer cells; its expression is, in part, dependent on ER{alpha} signaling. However, many ER{alpha}-negative tumors and tumor cell lines (e.g., SKBR3) also show over-expression of cyclin D1. This suggests that, in addition to ER{alpha} signaling, cyclin D1 expression is under the control of other signaling pathways; these pathways may even be over-expressed in the ER{alpha}-negative cells. We previously noticed that both ER{alpha}-positive and -negative cell lines over-express BRCA1-IRIS mRNA and protein. Furthermore, the level of over-expression of BRCA1-IRIS in ER{alpha}-negative cell lines even exceeded its over-expression level inmore » ER{alpha}-positive cell lines. In this study, we show that: (1) BRCA1-IRIS forms complex with two of the nuclear receptor co-activators, namely, SRC1 and SRC3 (AIB1) in an ER{alpha}-independent manner. (2) BRCA1-IRIS alone, or in connection with co-activators, is recruited to the cyclin D1 promoter through its binding to c-Jun/AP1 complex; this binding activates the cyclin D1 expression. (3) Over-expression of BRCA1-IRIS in breast cells over-activates JNK/c-Jun; this leads to the induction of cyclin D1 expression and cellular proliferation. (4) BRCA1-IRIS activation of JNK/c-Jun/AP1 appears to account for this, because in cells that were depleted from BRCA1-IRIS, JNK remained inactive. However, depletion of SRC1 or SRC3 instead reduced c-Jun expression. Our data suggest that this novel signaling pathway links BRCA1-IRIS to cellular proliferation through c-Jun/AP1 nuclear pathway; finally, this culminates in the increased expression of the cyclin D1 gene.« less
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