Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

Mao, Catherine D.; Byers, Stephen W.

doi:10.1615/critreveukargeneexpr.v21.i3.10

Cited by 71 publications

(74 citation statements)

References 244 publications

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“…Thus, MAPK signaling can influence Wnt target gene activation by regulating the protein stability of isoforms of TCF4 transcription factors. It has been shown that changes in the relative abundance of Tcf4 variants can indeed fine tune target gene expression in a cell-context-dependent manner (47). Because the Tcf4M/S proteins can bind β-catenin, we assume that by reducing these isoforms by MAPK inhibition, more β-catenin becomes accessible for canonical Wnt target gene activation through the large Tcf4E transcription factor.…”

Section: Discussionmentioning

confidence: 98%

Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine

Heuberger

Kosel²,

Qi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

141

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In the development of the mammalian intestine, Notch and Wnt/ β-catenin signals control stem cell maintenance and their differentiation into absorptive and secretory cells. Mechanisms that regulate differentiation of progenitors into the three secretory lineages, goblet, paneth, or enteroendocrine cells, are not fully understood. Using conditional mutagenesis in mice, we observed that Shp2-mediated MAPK signaling determines the choice between paneth and goblet cell fates and also affects stem cells, which express the leucine-rich repeat-containing receptor 5 (Lgr5). Ablation of the tyrosine phosphatase Shp2 in the intestinal epithelium reduced MAPK signaling and led to a reduction of goblet cells while promoting paneth cell development. Conversely, conditional mitogen-activated protein kinase kinase 1 (Mek1) activation rescued the Shp2 phenotype, promoted goblet cell and inhibited paneth cell generation. The Shp2 mutation also expanded Lgr5+ stem cell niches, which could be restricted by activated Mek1 signaling. Changes of Lgr5+ stem cell quantities were accompanied by alterations of paneth cells, indicating that Shp2/MAPK signaling might affect stem cell niches directly or via paneth cells. Remarkably, inhibition of MAPK signaling in intestinal organoids and cultured cells changed the relative abundance of Tcf4 isoforms and by this, promoted Wnt/β-catenin activity. The data thus show that Shp2-mediated MAPK signaling controls the choice between goblet and paneth cell fates by regulating Wnt/β-catenin activity.

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Section: Discussionmentioning

confidence: 98%

Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine

Heuberger

Kosel²,

Qi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

141

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“…TCF7 and LEF1 regulate transcription initiation by forming a coactivating complex with nuclear β-catenin. P53 and the nuclear receptor family may inhibit the Wnt signaling pathway by regulating TCF7/LEF1 activation or repression (38). AXIN2 (39) and MYC (40) are the targets in the classic Wnt signaling pathway, which modulates the stability of β-catenin to regulate cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile comparison between colorectal cancer and adjacent normal tissues

Yang

Mao

et al. 2017

Oncol Lett

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Abstract. The present study aimed to compare gene expression profiles between colorectal cancer and adjacent normal tissues, and to perform a preliminarily analysis of the key genes and underlying molecular mechanisms implicated in colorectal cancer development. Gene expression microarray chips were used to screen genes that were differently expressed between colorectal cancer and adjacent normal tissues. Approximately 1,183 genes were differentially expressed in cancer tissues compared with adjacent normal tissues (P≤0.05; fold difference, >2.0), of which 570 genes were upregulated and 613 genes were downregulated. In total, 6 upregulated genes, including keratin 23, collagen type X α1, collagen type XI α1, cell migration-inducing hyaluronan-binding protein, transforming growth factor-β1 and V-Myc avian myelocytomatosis viral oncogene homolog, and 2 downregulated genes, including channel α subunit 7 and EPH receptor A7, were selected and validated using reverse transcription-quantitative polymerase chain reaction, which exhibited results that were consistent with the microarray analysis. These 1,183 differentially expressed genes were further classified into 71 groups based on their functions using gene ontology and pathway analyses. Kyoto Encyclopedia of Genes and Genomes analysis of these upregulated or downregulated genes suggested that 23 signaling pathways were involved. The present study preliminarily screened for and identified key genes and signaling pathways that may be closely associated with colorectal cancer development. However, subsequent gene function studies are required to verify these findings. IntroductionColorectal cancer (CRC) is a common gastrointestinal cancer and its global incidence is outranked only by gastric and esophageal cancers (1). There were ~14.1 million new cases of cancer globally in 2012, of which CRC accounted for 1.4 million and in China, was surpassed only by lung and breast cancers (2). In China, the incidence of CRC and its mortality rate have been ranked third and fourth, respectively among malignant tumors (3). Studies have demonstrated that China's annual incidence of CRC increases twice as fast compared with the global average (3,4). In Shanghai, Beijing and Guangzhou, the incidence of colorectal cancer is 40/100,000 individuals (5); and a previous CRC survey program in Wuhan, Hubei province has reported a high incidence of 90/100,000 individuals, which is twice that of the national average (6). According to the National Bowel Cancer Screening Programme, whose aim was to reduce the incidence of symptomatic CRC, the majority of patients present with symptoms to their general practitioner (7-9). An isolated symptom may be associated with CRC, but typically symptoms were observed in clusters. In total ≥1 high-risk symptoms are seen in ~85% of patients with CRC, who were referred to secondary care (10). However, symptoms for disease may be biased to a certain extent by 'selection phenomena', and this is the case to CRC (11). When performing diagnostic research in second...

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“…CAL-101 and Indo blocked Akt phosphorylation and β-catenin expression in Th17 cells, but only temporarily, as these pathways rebounded to a greater extent (compared with untreated cells) after secondary antigen recall responses. Th17 cells treated with both drugs expressed higher lev- els of Tcf7, a critical protein in the Wnt/β-catenin pathway responsible for promoting T cell self-renewal (3,37,(41)(42)(43)(44). Moreover, the treated Th17 cells reexpressed β-catenin and phosphoAkt upon restimulation in vivo.…”

Section: Discussionmentioning

confidence: 98%