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TRIB2 在肝癌细胞中 Wnt/TCF 的下游发挥作用,以调节 YAP 和 C/EBPα 的功能。

TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPα function.

机构信息

Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

出版信息

Mol Cell. 2013 Jul 25;51(2):211-25. doi: 10.1016/j.molcel.2013.05.013. Epub 2013 Jun 13.


DOI:10.1016/j.molcel.2013.05.013
PMID:23769673
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4007693/
Abstract

Dysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the βTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/β-catenin, Hippo/YAP, and C/EBPα pathways in cancer cells.

摘要

Wnt 信号通路失调与人类肝癌的发生密切相关。然而,肝癌特异性的 Wnt 转录程序和下游效应物仍知之甚少。在这里,我们确定了 TRIB2 是肝癌中 Wnt/TCF 的直接靶标,并证明包括 TRIB2 在内的 Wnt 靶基因的转录是由肝癌细胞中的 TCF 和 FoxA 转录因子协调的。我们表明,Wnt-TRIB2 的激活对于癌细胞的存活和转化至关重要。在机制上,TRIB2 通过与βTrCP 泛素连接酶相互作用促进 YAP 转录共激活因子的蛋白质稳定。此外,我们发现 TRIB2 可以解除肝癌细胞中 C/EBPα 对 YAP/TEAD 转录激活的抑制作用。总之,我们的研究揭示了肝癌特异性 Wnt 转录输出的调控机制,并表明 TRIB2 作为信号枢纽,在癌细胞中整合了 Wnt/β-catenin、Hippo/YAP 和 C/EBPα 通路。

相似文献

[1]
TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPα function.

Mol Cell. 2013-6-13

[2]
TRIB2 inhibits Wnt/β-Catenin/TCF4 signaling through its associated ubiquitin E3 ligases, β-TrCP, COP1 and Smurf1, in liver cancer cells.

FEBS Lett. 2014-10-13

[3]
Downregulation of SLC5A8 inhibits hepatocellular carcinoma progression through regulation of Wnt/β-catenin signaling.

Tumour Biol. 2016-10

[4]
Impaired phosphorylation and ubiquitination by p70 S6 kinase (p70S6K) and Smad ubiquitination regulatory factor 1 (Smurf1) promote tribbles homolog 2 (TRIB2) stability and carcinogenic property in liver cancer.

J Biol Chem. 2013-10-2

[5]
Nitric oxide production upregulates Wnt/β-catenin signaling by inhibiting Dickkopf-1.

Cancer Res. 2013-9-5

[6]
Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway.

World J Surg Oncol. 2015-10-24

[7]
Overexpression of TRIB2 in human lung cancers contributes to tumorigenesis through downregulation of C/EBPα.

Oncogene. 2011-3-14

[8]
Wnt/β-catenin signaling regulates Yes-associated protein (YAP) gene expression in colorectal carcinoma cells.

J Biol Chem. 2012-2-15

[9]
EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis.

Cancer Res. 2011-4-21

[10]
Rab11a sustains GSK3β/Wnt/β-catenin signaling to enhance cancer progression in pancreatic cancer.

Tumour Biol. 2016-10

引用本文的文献

[1]
The Drosophila pseudokinase Tribbles translocates to the fat body membrane in response to fasting to modulate insulin sensitivity.

Development. 2025-4-15

[2]
The Role of Yes-Associated Protein in Inflammatory Diseases and Cancer.

MedComm (2020). 2025-3-10

[3]
Potential biomarkers and immune infiltration linking endometriosis with recurrent pregnancy loss based on bioinformatics and machine learning.

Front Mol Biosci. 2025-2-3

[4]
The role of tribbles homolog 2 in cell proliferation.

Cell Commun Signal. 2025-1-6

[5]
Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2.

Eur J Med Chem. 2025-1-5

[6]
Decoding the Role of O-GlcNAcylation in Hepatocellular Carcinoma.

Biomolecules. 2024-7-25

[7]
Targeting the Hippo/YAP1 signaling pathway in hepatocellular carcinoma: From mechanisms to therapeutic drugs (Review).

Int J Oncol. 2024-9

[8]
Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review).

Int J Oncol. 2024-7

[9]
Wnt/β-catenin signaling regulates amino acid metabolism through the suppression of CEBPA and FOXA1 in liver cancer cells.

Commun Biol. 2024-4-29

[10]
Beta-Transducin Repeats-Containing Proteins as an Anticancer Target.

Cancers (Basel). 2023-8-24

本文引用的文献

[1]
β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis.

Cell. 2012-12-13

[2]
Restriction of intestinal stem cell expansion and the regenerative response by YAP.

Nature. 2012-11-25

[3]
Wnt/β-catenin signaling and disease.

Cell. 2012-6-8

[4]
FoxA1 is a key mediator of hormonal response in breast and prostate cancer.

Front Endocrinol (Lausanne). 2012-5-18

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The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis.

Proc Natl Acad Sci U S A. 2012-4-9

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Wnt signaling, stem cells, and cancer of the gastrointestinal tract.

Cold Spring Harb Perspect Biol. 2012-4-1

[7]
A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic self-renewal.

Mol Cell Biol. 2012-3-5

[8]
Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer.

Cell. 2012-1-20

[9]
Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers.

Gastroenterology. 2011-12-8

[10]
Coordinating developmental signaling: novel roles for the Hippo pathway.

Trends Cell Biol. 2011-12-5

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