ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with β-catenin defects and promotes neoplastic transformation

Kolligs, Frank T.; Nieman, Marvin T.; Winer, Ira; Hu, Gang; Mater, David Van; Feng, Ying; Smith, Ian; Wu, Rong; Zhai, Yali; Cho, Kathleen R.; Fearon, Eric R.

doi:10.1016/s1535-6108(02)00035-1

Cited by 137 publications

(107 citation statements)

References 59 publications

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“…Activation of selected target genes, such as Cyclin-D1 (Shtutman et al, 1999;Tetsu and McCormick, 1999), IGF2 (Longo et al, 2002) and TCF4 (Kolligs et al, 2002) was measured by real-time semi quantitative PCR ( Figure 2c). Significant increases of Cyclin-D1 (2.45 ± 0.32-and 1.86 ± 0.25-fold increase) and IGF2 expression (2.9 ± 0.07-and 1.38 ± 0.09-fold increase) were detected in LAN-1-R and IGRN-91-R, respectively.…”

Section: Identification Of Differentially Expressed Genes In Chemoresmentioning

confidence: 99%

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

et al. 2009

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The development of chemoresistance represents a major obstacle in the successful treatment of cancers such as neuroblastoma (NB), a particularly aggressive childhood solid tumour. The mechanisms underlying the chemoresistant phenotype in NB were addressed by gene expression profiling of two doxorubicin (DoxR)-resistant vs sensitive parental cell lines. Not surprisingly, the MDR1 gene was included in the identified upregulated genes, although the highest overexpressed transcript in both cell lines was the frizzled-1 Wnt receptor (FZD1) gene, an essential component of the Wnt/b-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/b-catenin pathway as revealed by nuclear b-catenin translocation and target genes transactivation. Interestingly, specific microadapted short hairpin RNA (shRNAmir)-mediated FZD1 silencing induced parallel strong decrease in the expression of MDR1, another b-catenin target gene, revealing a complex, Wnt/b-catenin-mediated implication of FZD1 in chemoresistance. The significant restoration of drug sensitivity in FZD1-silenced cells confirmed the FZD1-associated chemoresistance. RNA samples from 21 patient tumours (diagnosis and postchemotherapy), showed a highly significant FZD1 and/or MDR1 overexpression after treatment, underlining a role for FZD1-mediated Wnt/b-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/b-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.

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Section: Identification Of Differentially Expressed Genes In Chemoresmentioning

confidence: 99%

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

et al. 2009

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“…This is best exemplified by the classical β-catenin, which, as the downstream effector of the Wnt signaling pathway, translocates to the nucleus and binds to the Lef/TCF transcription factor (reviewed by Gumbiner, 1995;Peifer, 1995). Within the nucleus, the β-catenin/TCF heterodimer then activates tumorigenesis-associated genes such as cyclinD1, c-myc, matrilysin, Id2 and ITF-2 (Crawford et al, 1999;He et al, 1998;Kolligs et al, 2002;Rockman et al, 2001;Shtutman et al, 1999). Our identification of the novel BTB/POZ transcriptional repressor Kaiso as a p120 ctnspecific binding partner (Daniel and Reynolds, 1999) thus raised the exciting possibility that p120 ctn , like β-catenin, regulates gene expression.…”

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confidence: 99%

NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

Kelly

Spring

Otchere

et al. 2004

Journal of Cell Science

104

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IntroductionThe Armadillo catenins, β-, γ-and p120 ctn , are multifunctional proteins whose malfunction contributes to tumor progression by various means (Behrens, 1999;Van Aken et al., 2001). They are members of a larger family of Armadillo proteins that are characterized by the presence of an Armadillo domain consisting of ten or more tandem copies of a 42 amino-acid Armadillo repeat (Peifer et al., 1994). The importance of the Armadillo catenins in tumorigenesis was first credited to their involvement in the multiprotein cadherin-catenin complex, which forms the major cell-cell adhesion system in epithelial cells. Dysfunction of this complex, through defects in any of its components, correlates with the metastatic phenotype iñ 50% of human carcinomas (Behrens, 1999;Yap, 1998). The key participant in this complex is the transmembrane glycoprotein and tumor suppressor E-cadherin that mediates cell-cell adhesion by the homophilic interactions of its extracellular domain. E-cadherin is then anchored to the underlying actin cytoskeleton by the classical catenin cofactors, β-and γ-catenin, that bind E-cadherin in a mutually exclusive manner (reviewed by Nollet et al., 1999). These classical catenins bind simultaneously to a highly conserved carboxy-terminal domain of E-cadherin and to the actinbinding protein α-catenin (reviewed by Behrens, 1999;Rimm et al., 1995). Like β-and γ-catenin, the nonclassical Armadillo catenin p120 ctn binds the cytoplasmic tail of E-cadherin via its Arm domain Reynolds et al., 1992). However, β-and γ-catenin compete for binding to the distal conserved catenin-binding domain, and function by anchoring E-cadherin to the actin cytoskeleton, whereas p120 ctn binds Ecadherin at a distinct juxtamembrane domain (JMD) and does not interact with α-catenin (Daniel and Reynolds, 1995;Thoreson et al., 2000). Importantly, the JMD is implicated in E-cadherin stability (Ireton et al., 2002;Pettitt et al., 2003), modulating cadherin adhesive strength (Aono et al., 1999;Ohkubo and Ozawa, 1999;Thoreson et al., 2000;Yap et al., 1998) and regulating cytoskeletal dynamics Grosheva et al., 2001;Noren et al., 2000), and as such p120 ctn is speculated to be a key mediator of these effects. This hypothesis is supported by recent observations that p120 ctn modulates the activities of RhoA, Rac and Cdc42, which are key mediators of cytoskeletal organization Grosheva et al., 2001;Noren et al., 2000).Originally identified as a Src kinase substrate (Reynolds et al., 1989), it was the structural similarity of p120 ctn to β-catenin that led to the discovery of p120 ctn as a novel catenin component of the cadherin complex (Daniel and Reynolds, 2675The Armadillo catenin p120 ctn regulates cadherin adhesive strength at the plasma membrane and interacts with the novel BTB/POZ transcriptional repressor Kaiso in the nucleus. The dual localization of p120 ctn at cell-cell junctions and in the nucleus suggests that its nucleocytoplasmic trafficking is tightly regulated. Here we report on the identification of a specific and h...

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“…19 Although the complete list of the target genes is still not available, cyclin D1 and c-myc, two essential transcription factors in cell growth and apoptosis regulation, are among the target genes. 20,21 The other recently identified potential targets include ITF-2 (immunoglobulin transcription factor-2), 22 glutamine synthetase, 23 and inositol hexakisphosphate kinase 2 (IP6K2). 24 It is generally agreed that b-catenin is an important mediator in the Wnt/b-catenin signaling pathway.…”

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confidence: 99%

Stabilized β-catenin promotes hepatocyte proliferation and inhibits TNFα-induced apoptosis

Shang

Zhu

Lin

et al. 2004

Laboratory Investigation

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The human hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The mechanisms of liver cell oncogenic transformation are still unknown. The b-catenin mutations are identified in up to 30% of HCC and 80% of hepatoblastoma, suggesting a potential role of b-catenin in the pathogenesis of liver cancers. To define the biological role of the stabilized b-catenin in liver cell growth and transformation, we examined the effect of mutant b-catenin on an immortalized murine hepatocyte cell line, AML12. A cell line that stably expresses mutant b-catenin was established. The cell proliferation, apoptosis, and cell transformation of this cell line were characterized. Our data indicate that the stabilized b-catenin enhances hepatocyte proliferation, suppresses TNFa/Act D-induced cell apoptosis, and causes weak anchorage-independent cell growth. The stabilized b-catenin-containing cells did not develop tumor in immune-deficient mice. The target genes, c-myc and cyclin D1, were activated by b-catenin in the hepatocytes. Our study suggests that mutant b-catenin can promote cell proliferation and cell survival ability, but the stabilized b-catenin alone is insufficient for completely oncogenic transformation.

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ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with β-catenin defects and promotes neoplastic transformation

Cited by 137 publications

References 59 publications

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

Stabilized β-catenin promotes hepatocyte proliferation and inhibits TNFα-induced apoptosis

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