Synergy between LRH-1 and β-Catenin Induces G1 Cyclin-Mediated Cell Proliferation

Botrugno, Oronza A.; Fayard, Elisabeth; Annicotte, Jean-Sébastien; Haby, Christelle; Brennan, Thomas J.; Wendling, Olivia; Tanaka, Toshiya; Kodama, Tatsuhiko; Thomas, Winston; Auwerx, Johan; Schoonjans, Kristina

doi:10.1016/j.molcel.2004.07.009

Cited by 257 publications

(343 citation statements)

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“…This idea is reinforced by the observation that LRH-1 overexpression triggers proliferation of pancreatic and hepatic cancer cell lines (Botrugno et al, 2004). Furthermore, it has been recently demonstrated that LRH-1 þ /À mice are protected from colon carcinogenesis (Schoonjans et al, 2005).…”

Section: Discussionmentioning

confidence: 97%

“…Several studies reported elevated expression of LRH-1 in granulosa cells and corpus luteum of the ovary, suggesting potential functions for this nuclear receptor in follicular growth and function (Falender et al, 2003;Hinshelwood et al, 2003). By controlling expression of cyclin E1 and D1 through interaction with b-catenin, LRH-1 has recently been shown to promote intestinal cell renewal (Botrugno et al, 2004). However, despite its transcriptional control on G1 phase cyclins, the contribution of LRH-1 to tumorigenesis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

et al. 2005

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Liver receptor homolog-1 (LRH-1) is a nuclear receptor previously known to have distinct functions during mouse development and essential roles in cholesterol homeostasis. Recently, a new role for LRH-1 has been discovered in tumor progression, giving LRH-1 potential transforming functions. In order to identify critical factors stimulating LRH-1 expression leading to deregulated cellular proliferation, we studied its expression and its regulation in several breast cancer cell lines. We observed that LRH-1 expression was increased in estrogen receptor (ER) a expressing cell lines, whereas weak-to-no expression was found in nonexpressing ERa cell lines. In MCF7, LRH-1 expression was highly induced after treatment with 17b-estradiol (E2). This transcriptional regulation was the result of a direct binding of the ER to the LRH-1 promoter, as demonstrated by gelshift and chromatin immunoprecipitation assays. Interestingly, siRNA-mediated inactivation of LRH-1 decreased the E2-dependent proliferation of MCF7 cells. Finally, LRH-1 protein expression was detected by immunohistochemistry in tumor cells of human mammary ductal carcinomas. Altogether, these data demonstrate that LRH-1 is transcriptionally regulated by the ER a and reinforce the hypothesis that LRH-1 could exert potential oncogenic effects during breast cancer formation.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

et al. 2005

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“…The ability of PPARg to bind h-catenin and regulate h-catenin/Tcf activity is shared with other nuclear receptors like the orphan nuclear receptor LRH1 and the androgen receptor. LRH1 was suggested to serve as a direct coactivator for Tcf/h-catenin transactivation from the cyclin D1 promoter (37). Androgen receptor can sequester h-catenin from Tcf4 or promote h-catenin/Tcf4 interaction depending on the biological system analyzed (38,39).…”

Section: Discussionmentioning

confidence: 99%

“…5C). The proposed mechanisms for FH535 activity are not mutually exclusive because the LRH1/ h-catenin complex coactivates Tcf4 at the cyclin D1 promoter and also regulates cyclin E1 transcription by direct binding to the LRH1-RE site in the cyclin E1 promoter (37).…”

Section: Discussionmentioning

confidence: 99%

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Handeli

Simon

2008

Molecular Cancer Therapeutics

161

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Activation of the Wnt/B-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based B-catenin/Tcf -responsive reporter. We identified FH535, a compound that suppresses both Wnt/B-catenin and peroxisome proliferator -activated receptor (PPAR) signaling. FH535 antagonizes both PPAR; and PPARD ligand -dependent activation and shows structural similarity to GW9662, a known PPAR; antagonist. The effect of FH535 on B-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARd gene, as well as by the PPAR; agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators B-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of B-catenin recruitment, in comparison with GW9662, is linked to FH535 ¶s unique capability to inhibit the Wnt/B-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer. [Mol Cancer Ther 2008;7(3):521 -9]

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“…We also determined the kinase activity of Cdc2 on histone H1 substrate, and confirmed its reduction in Wnt-activated cells (Figure 3f). In contrast, expression levels remained unchanged for Cdc2, cyclin B and Wnt-target gene products cyclin D1 (Tetsu and McCormick, 1999) and E1 (Botrugno et al, 2004), c-myc (He et al, 1998), and p21 (van de Wetering et al, 2002) (Figure 3e, Supplementary Figure 3, and data not shown). We obtained essentially the same results with colcemid-treated cells as well (Supplementary Figure 3).…”

Section: Es Cells With High Abi Produce New Chromosomal Aberrationsmentioning

confidence: 93%

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Aoki

Sugai

et al. 2006

Oncogene

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Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate b-catenin/ T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or b-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signalactivated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear b-catenin, ABI was significantly higher than in those without. These results collectively indicate that b-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

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Synergy between LRH-1 and β-Catenin Induces G1 Cyclin-Mediated Cell Proliferation

Cited by 257 publications

References 46 publications

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

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