Modulation of Transcriptional Regulation by LEF-1 in Response to Wnt-1 Signaling and Association with β-Catenin

Hsu, Shu-Chi; Galceran, Juan; Grosschedl, Rudolf

doi:10.1128/mcb.18.8.4807

Cited by 353 publications

(375 citation statements)

References 76 publications

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“…Cartilage extracts containing FRZB have in vivo chondrogenic activity. [31][32][33] In our study, FRZB was down-regulated in OA synovium and cartilage and in RA cartilage. Therefore, FRZB might be also involved in human joint cartilage destruction.…”

Section: Discussionmentioning

confidence: 70%

Expression Profiles and Functional Analyses of Wnt-Related Genes in Human Joint Disorders

Nakamura

Nawata

Wakitani

2005

The American Journal of Pathology

110

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Section: Discussionmentioning

confidence: 70%

Expression Profiles and Functional Analyses of Wnt-Related Genes in Human Joint Disorders

Nakamura

Nawata

Wakitani

2005

The American Journal of Pathology

110

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“…We and others have demonstrated that Wnt-1 or Dvl1, when expressed in NIH3T3 cells, can activate the transcription regulator 16,28,29). This activation depends on β-catenin and is suppressed by GSK-3β and axin.…”

Section: Dep Domain Interacts With Upstream Regulators Of Dvlmentioning

confidence: 79%

Untitled

et al. 2000

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The DEP domain of Dishevelled (Dvl) proteins transduces signals to effector proteins downstream of Dvl in the Wnt pathway. Here we report that DEP-containing mutants inhibit Wnt-induced, but not Dvl-induced, activation of the transcription factor Lef-1. This inhibitory effect is weakened by a K434M mutation. Nuclear magnetic resonance spectroscopy revealed that the DEP domain of mouse Dvl1 comprises a three-helix bundle, a β-hairpin 'arm' and two short β-strands at the Cterminal region. Lys 434 is located at the tip of the β-hairpin 'arm'. Based on our findings, we conclude that DEP interacts with regulators upstream of Dvl via a strong electric dipole on the molecule's surface created by Lys 434, Asp 445 and Asp 448; the electric dipole and the putative membrane binding site are at two different locations.The Wnt signaling pathway is a key regulatory pathway for cellular development and growth. Wnt signaling has been extensively studied in Drosophila, Caenorhabditis elegans, Xenopus, and mammalian systems [1][2][3][4][5] . Through genetic studies, a working model of the Wnt signaling pathway has been established. Secreted Wnt proteins bind to Frizzled transmembrane receptors. The receptor-ligand complex activates the Dishevelled (Dsh and Dvl) proteins, which suppress the activity of glycogen synthase kinase-3β (GSK-3β). If its activity is not suppressed, GSK-3β binds to adenomatous polyposis coli (APC) protein and axin and then phosphorylates specific Ser and Thr residues at the N-terminus of β-catenin. In turn, the ubiquitin-proteasome pathway rapidly degrades hyperphosphorylated β-catenin. Wnt activation prevents this process by promoting the cytosolic accumulation and subsequent translocation of β-catenin into the nucleus. Once in the nucleus, β-catenin binds to the transcription factors T-cell factor (Tcf) or lymphoid enhancer factor (Lef) and acts as a transcriptional coactivator 5 . The result is increased expression of Tcf or Lef regulated target genes, such as Myc 6 and the gene encoding cyclin D 7 .© 2000 Nature America Inc. Correspondence should be addressed to: J.Z. Jie.Zheng@stjude.org. HHS Public Access DEP domain interacts with upstream regulators of DvlWe and others have demonstrated that Wnt-1 or Dvl1, when expressed in NIH3T3 cells, can activate the transcription regulator 16,28,29). This activation depends on β-catenin and is suppressed by GSK-3β and axin. To characterize the role of the mDvl1 DEP domain in Wnt signaling, we examined the effect of the Dvl1 N-terminal truncation mutant, DvlC1, on Wnt-induced activation of the transcription factor Lef-1. In Lef dependent reporter gene assays, DvlC1 inhibited Wnt-1 induced Lef-1 activation but not Dvl1 induced Lef-1 activation (Fig. 2). To further characterize the specific sequences that inhibit the Wnt-induced activation, we generated two additional mutants of mDvl1: DvlDEP, which contains only the DEP domain; and DvlC2, which encompasses the sequence downstream of the DEP domain. When expressed in NIH3T3 cells, DvlDEP, like DvlC1, bloc...

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“…To directly test whether PTEN could affect TCF transcription activity, we examined the PTEN influence on the activity of a LEF-1-luciferase reporter, which contains classical LEF-1-binding sites (Hsu et al, 1998). As shown in Figure 4f, exogenous expression of PTEN in Pten-null MEFs reduced the LEF-mediated (Figure 5a), and previous studies have shown that CREB can bind to this CRE (Sicinski et al, 1996).…”

Section: Suppression Of Cyclin D2 Expression By Pten W Huang Et Almentioning

confidence: 94%

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

Huang

et al. 2006

Oncogene

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PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3b and b-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3b, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3b/b-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.

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Modulation of Transcriptional Regulation by LEF-1 in Response to Wnt-1 Signaling and Association with β-Catenin

Cited by 353 publications

References 76 publications

Expression Profiles and Functional Analyses of Wnt-Related Genes in Human Joint Disorders

Expression Profiles and Functional Analyses of Wnt-Related Genes in Human Joint Disorders

Untitled

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

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