Wnt signaling and colon carcinogenesis: Beyond APC

Najdi, Rani; Holcombe, Randall F.; Waterman, Marian L.

doi:10.4103/1477-3163.78111

Cited by 178 publications

(132 citation statements)

References 96 publications

(129 reference statements)

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“…However, there are still four family members existing as differently spliced variants that are all expressed in different combinations and at different stages of development (Najdi et al 2011). Moreover, some of these transcription factors have been shown to act-in addition to their role as activators-also as repressors of target genes in the absence of Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

Probing transcription-specific outputs of β-catenin in vivo

et al. 2011

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b-Catenin, apart from playing a cell-adhesive role, is a key nuclear effector of Wnt signaling. Based on activity assays in Drosophila, we generated mouse strains where the endogenous b-catenin protein is replaced by mutant forms, which retain the cell adhesion function but lack either or both of the N-and the C-terminal transcriptional outputs. The C-terminal activity is essential for mesoderm formation and proper gastrulation, whereas N-terminal outputs are required later during embryonic development. By combining the double-mutant b-catenin with a conditional null allele and a Wnt1-Cre driver, we probed the role of Wnt/b-catenin signaling in dorsal neural tube development. While loss of b-catenin protein in the neural tube results in severe cell adhesion defects, the morphology of cells and tissues expressing the double-mutant form is normal. Surprisingly, Wnt/b-catenin signaling activity only moderately regulates cell proliferation, but is crucial for maintaining neural progenitor identity and for neuronal differentiation in the dorsal spinal cord. Our model animals thus allow dissecting signaling and structural functions of b-catenin in vivo and provide the first genetic tool to generate cells and tissues that entirely and exclusively lack canonical Wnt pathway activity.[Keywords: canonical Wnt signaling; signaling versus structural function of b-catenin; mouse strains expressing transcriptionally inactive b-catenin; cell fate determination in the dorsal neural tube]

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Section: Discussionmentioning

confidence: 99%

Probing transcription-specific outputs of β-catenin in vivo

et al. 2011

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“…These alterations are responsible for responsiveness or resistance to antitumor agents (Figure 2), and they can confer individual susceptibility to cancers when they are germlines [Markowitz and Bertagnolli, 2009;Najdi et al 2011;De Rosa et al 2015].…”

Section: Molecular Heterogeneity Of Colorectal Cancermentioning

confidence: 99%

The biological complexity of colorectal cancer: insights into biomarkers for early detection and personalized care

Rosa

Rega

Costabile

et al. 2016

Therap Adv Gastroenterol

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Colorectal cancer has been ranked the third and second most prevalent of all cancers in men and women, respectively, and it represents the fourth most common cause of cancer deaths. In 2012, there were 1.4 million estimated cases of colorectal cancer worldwide, and 700,000 estimated deaths, which implies significant impact on public health, especially in economically-developed countries. In recent years, there has been an increase in the number of tumors, although this has been accompanied by decreased mortality, due to more appropriate and available information, earlier diagnosis, and improvements in treatment. Colorectal cancers are characterized by great genotypic and phenotypic heterogeneity, including tumor microenvironment and interactions between healthy and cancer cells. All of these traits confer a unique peculiarity to each tumor, which can thus be considered as an individual disease. Well conducted molecular and clinical characterization of each colorectal cancer is essential with a view to the implementation of precision oncology, and thus personalized care. This last aims at standardization of therapeutic plans chosen according to the genetic background of each specific neoplasm, to increase overall survival and reduce treatment side effects. Thus, prognostic and predictive molecular biomarkers assume a critical role in the characterization of colorectal cancer and in the determination of the most appropriate therapy

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“…Wnt activating mutations are found in a broad range of solid tumors including colon cancer, gastric cancer, hepatocellular carcinoma, breast cancer, medulloblastoma, melanoma, non-small cell lung cancer, pancreas adenocarcinoma, and prostate cancer (20). It has been well established that the majority of intestinal neoplasia with deregulated Wnt signaling harbor truncating mutations in both alleles of the APC tumor suppressor gene (21).…”

Section: Introductionmentioning

confidence: 99%

A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice

Waaler

Machoň

Tůmová³

et al. 2012

Cancer Research

302

267

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Increased nuclear accumulation of b-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/b-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the b-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the b-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the b-catenin destruction complex, followed by increased degradation of b-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of b-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/b-catenin signaling through inhibiting the PARP domain of TNKS1/2. Cancer Res; 72(11); 2822-32. Ó2012 AACR.

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Wnt signaling and colon carcinogenesis: Beyond APC

Cited by 178 publications

References 96 publications

Probing transcription-specific outputs of β-catenin in vivo

Probing transcription-specific outputs of β-catenin in vivo

The biological complexity of colorectal cancer: insights into biomarkers for early detection and personalized care

A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice

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