Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human Ls174T CRC cells with induced of dnTCF-4

ABSTRACT: The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Cornelis Verweij

PROVIDER: E-SMDB-1723 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.

van de Wetering Marc M Sancho Elena E Verweij Cornelis C de Lau Wim W Oving Irma I Hurlstone Adam A van der Horn Karin K Batlle Eduard E Coudreuse Damien D Haramis Anna Pavlina AP Tjon-Pon-Fong Menno M Moerer Petra P van den Born Maaike M Soete Gwen G Pals Steven S Eilers Martin M Medema Rene R Clevers Hans H

Cell 20021001 2

The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of ...[more]

PMID: 12408868

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Project description:Heldt2018 - Proliferation-quiescence decision in response to DNA damage This model is described in the article: A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells. Heldt FS, Barr AR, Cooper S, Bakal C, Novák B. Proc. Natl. Acad. Sci. U.S.A. 2018 Feb; : Abstract: Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation-quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli. This model is hosted on BioModels Database and identified by: MODEL1703030000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Transcription profiling of human Ls174T CRC cells with induced of dnTCF-4

Publications

The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.

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