T-cell factor 4 (TCF4), together with β-catenin coactivator, functions as the major transcriptional mediator of the canonical wingless/integrated (Wnt) signaling pathway in the intestinal epithelium. The pathway activity is essential for both intestinal homeostasis and tumorigenesis. To date, several mouse models and cellular systems have been used to analyze TCF4 function. However, some findings were conflicting, especially those that were related to the defects observed in the mouse gastrointestinal tract after Tcf4 gene deletion, or to a potential tumor suppressive role of the gene in intestinal cancer cells or tumors. Here, we present the results obtained using a newly generated conditional Tcf4 allele that allows inactivation of all potential Tcf4 isoforms in the mouse tissue or small intestinal and colon organoids. We also employed the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to disrupt the TCF4 gene in human cells. We showed that in adult mice, epithelial expression of Tcf4 is indispensable for cell proliferation and tumor initiation. However, in human cells, the TCF4 role is redundant with the related T-cell factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1) transcription factors.

• Klíčová slova
• TCF7L2, Wnt signaling, colorectal cancer, conditional gene inactivation, epithelium, gut, organoids, tumorigenesis,
• Publikační typ
• časopisecké články MeSH

In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity.

• Klíčová slova
• Hippo pathway, LGR, R-Spondins, Wnt/β-catenin signalling, YAP1/TAZ, colorectal cancer,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. The mammalian TCF/LEF family comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known as TCF1, LEF1, TCF3, and TCF4, respectively). The proteins display common structural features and are often expressed in overlapping patterns implying their redundancy. Such redundancy was indeed observed in gene targeting studies; however, individual family members also exhibit unique features that are not recapitulated by the related proteins. In the present viewpoint, we summarized our current knowledge about the specific features of individual TCFs, namely structural-functional studies, posttranslational modifications, interacting partners, and phenotypes obtained upon gene targeting in the mouse. In addition, we employed several publicly available databases and web tools to evaluate the expression patterns and production of gene-specific isoforms of the TCF/LEF family members in human cells and tissues.

• Klíčová slova
• Fantom5, GTEx, Wnt signaling, splicing isoforms, the Cancer Genome Atlas,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.

• MeSH
• anoikis MeSH
• buněčný rodokmen MeSH
• časové faktory MeSH
• chemokin CXCL12 metabolismus   MeSH
• endoteliální buňky metabolismus   patologie   MeSH
• epitelové buňky účinky léků   metabolismus   patologie   MeSH
• kadheriny metabolismus   MeSH
• lidé MeSH
• lymfocyty metabolismus   patologie   MeSH
• mezibuněčná komunikace MeSH
• myši transgenní MeSH
• myši MeSH
• nádorová transformace buněk genetika   metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   patologie   MeSH
• nádorové mikroprostředí * MeSH
• nádory žaludku farmakoterapie   genetika   metabolismus   patologie   MeSH
• nika kmenových buněk * MeSH
• protein Wnt 5a MeSH
• proteiny Wnt metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• receptory CXCR4 metabolismus   MeSH
• Rho proteiny vázající GTP metabolismus   MeSH
• rhoA protein vázající GTP MeSH
• signální dráha Wnt MeSH
• signální transdukce MeSH
• stárnutí buněk MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• transplantace kostní dřeně MeSH
• žaludeční sliznice účinky léků   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BHLHA15 protein, human MeSH Prohlížeč
• Bhlha15 protein, mouse MeSH Prohlížeč
• chemokin CXCL12 MeSH
• Cxcl12 protein, mouse MeSH Prohlížeč
• CXCR4 protein, mouse MeSH Prohlížeč
• kadheriny MeSH
• protein Wnt 5a MeSH
• proteiny Wnt MeSH
• protinádorové látky MeSH
• receptory CXCR4 MeSH
• Rho proteiny vázající GTP MeSH
• rhoA protein vázající GTP MeSH
• RhoA protein, mouse MeSH Prohlížeč
• transkripční faktory bHLH MeSH
• Wnt5a protein, mouse MeSH Prohlížeč