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Last update 23 Jan 2025

TBL1X

Last update 23 Jan 2025

Basic Info

Synonyms

EBI, F-box-like/WD repeat-containing protein TBL1X, SMAP55

+ [5]

Introduction

F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units (PubMed:14980219). Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange (PubMed:21240272).

Drugs associated with TBL1X

Tegatrabetan

Target

TBL1X

Mechanism

TBL1X inhibitors

Active Org.

Iterion Therapeutics, Inc. [+1]

Originator Org.

Iterion Therapeutics, Inc.

Active Indication

Acute Myeloid Leukemia [+9]

Inactive Indication

Aggressive Fibromatosis

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TD-11

Target

TBL1X

Mechanism

TBL1X inhibitors

Active Org.

The Ohio State University

Originator Org.

The Ohio State University

Active Indication

Diffuse Large B-Cell Lymphoma

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with TBL1X

NCT05797805

/ RecruitingPhase 1/2

A Phase 1/2 Exploratory Study of the TBL1 Inhibitor, Tegavivint (BC2059), in Patients With Advanced Hepatocellular Carcinoma

This study will be conducted in 2 parts. The first part is a phase 1 single-agent dose escalation,optimization, and expansion study of tegavivint in patients with advanced HCC after failure of at least one line of prior systemic therapy. In the second part of the study, the combination of tegavivint plus pembrolizumab will be assessed with a limited dose escalation followed by a randomized dose optimization.

Start Date13 Sep 2023

Sponsor / Collaborator

Iterion Therapeutics, Inc.

NCT05755087

/ RecruitingPhase 1IIT

Phase Ib Trial of Tegavivint in Patients with Relapsed/Refractory C-MYC Overexpressing Large B-Cell Lymphoma

This phase I trial tests the safety, side effects, and best dose of tegavivint in treating patients with large b-cell lymphomas that has come back (relapsed) or does not respond to treatment (refractory). Tegavivint may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving tegavivint may help control the disease.

Start Date06 Mar 2023

Sponsor / Collaborator

Ohio State University Comprehensive Cancer Center

NCT04780568

/ RecruitingPhase 1IIT

A Phase Ib Study of AZD9291 (Osimertinib) and BC2059 (Tegavivint) As First-Line Therapy in Patients with Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase Ib trial is to find out the best dose, possible benefits and/or side effects of osimertinib and tegavivint as first-line therapy in treating patients with EGFR-mutant non-small cell lung cancer that has spread to other places in the body (metastatic). Osimertinib and tegavivint may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date18 Jan 2022

Sponsor / Collaborator

Ohio State University Comprehensive Cancer Center

100 Clinical Results associated with TBL1X

100 Translational Medicine associated with TBL1X

0 Patents (Medical) associated with TBL1X

153

Literatures (Medical) associated with TBL1X

01 Jan 2025·Cancer Science

PPM1G‐mediated TBL1X mRNA splicing promotes cell migration in hepatocellular carcinoma

Article

Author: Su, Shu‐Guang ; Shi, Xinyu ; Zhang, Chris Zhiyi ; Hu, Liling ; Zheng, Dandan ; Shi, Fujin ; Liu, Danya ; Zhang, Meifang ; Li, Yuying ; Yuan, Xiaoyi

AbstractThe progression of hepatocellular carcinoma (HCC) is coincident with aberrant splicing of numerous tumor‐related genes. Identification of the tumor‐specific splice variants that facilitate HCC metastasis may provide a more comprehensive insight into the mechanisms of HCC metastasis. Through RNA sequencing and bioinformatic analyses, PPM1G was identified as a biomarker associated with HCC metastasis. Our data mapped a transcriptome‐wide landscape of alternative splicing events modulated by PPM1G in HCC. Notably, we characterized the exon six‐skipping transcript of TBL1X as an onco‐splice variant regulated by PPM1G. Experimental validation revealed the enrichment of TBL1X‐S in response to PPM1G overexpression. Moreover, mRNA stability analyses revealed that PPM1G prolonged the half‐life of the TBL1X‐S transcript. Both PPM1G and TBL1X‐S exhibited metastasis‐promoting phenotypes, with PPM1G‐driven metastasis in HCC being partially dependent on TBL1X‐S. Mechanistically, different TBL1X splice variants showed varying affinities for ZEB1, with TBL1X‐S significantly enhancing ZEB1 activation and repressing CDH1 transcription, potentially accelerating the epithelial‐mesenchymal transition (EMT) process. In conclusion, our study highlights the biological role of PPM1G and TBL1X‐S in tumor metastasis. The PPM1G/TBL1X‐S signaling axis presents a new view for investigating liver cancer metastasis mechanisms.

01 Dec 2024·Journal of Alzheimer’s Disease

Investigating gene expression datasets of hippocampus tissue to discover Alzheimer's disease-associated molecular markers

Article

Author: Thakur, Sonu Chand ; Sajad, Mohd ; Shamsi, Anas ; Prabha, Sneh ; Anjum, Farah ; Hassan, Md Imtaiyaz

Background Alzheimer's disease (AD) is an advancing neurodegenerative disorder distinguished by the formation of amyloid plaques and neurofibrillary tangles in the human brain. Nevertheless, the lack of peripheral biomarkers that can detect the development of AD remains a significant limitation. Objective The main aim of this work was to discover the molecular markers associated with AD. Methods We conducted a comprehensive microarray analysis of gene expression data from hippocampus tissue in AD patients and control samples using three microarray datasets (GSE1297, GSE28146, and GSE29378) collected from Gene Expression Omnibus (GEO). The datasets were pre-processed and normalized, revealing 346 significant genes, 103 of which were upregulated and 243 downregulated. The PPI network of significant genes was constructed to detect the top 50 hub genes, which were then further analyzed using Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), and GSEA, revealing 47 key genes involved in AD-related pathways. These key genes were then subjected to feed forward loop (FFL) motif analysis for the prediction of transcriptional factors (TFs) and microRNAs (miRNAs) mediated gene regulatory networks. Results The interaction of AD-associated TFs HNF4A, SPI1, EGR1, STAT3, and MYC and miRNAs hsa-miR-155-5p and hsa-miR-16-5p in the transcriptional and post-transcriptional events of 3 upregulated and 10 downregulated genes: H2AFZ, MCM3, MYO1C, AXIN1, CCND1, ETS2, MYH9, RELA, RHEB, SOCS3, TBL1X, TBP, TXNIP, and YWHAZ, respectively, has been identified. The miRNA/TF-mediated three types of the FFL motifs, i.e., miRNA-FFL, TF-FFL, and composite-FFL, were constructed, and seven common genes among these FFL were identified: CCND1, MYH9, SOCS3, RHEB, MYO1C, TXNIP, AXIN1, and TXNIP. Conclusions These findings may provide insights into the development of potential molecular markers for therapeutic management of AD.

01 Nov 2024·Gene

Analysis of genes differentially expressed in the cortex of mice with the Tbl1xr1 variant

Article

Author: Falize, Kim ; Boelen, Anita ; Bruinstroop, Eveline ; van Trotsenburg, Paul ; Hu, Yalan ; Hennekam, Raoul C ; Fliers, Eric ; Lauffer, Peter ; Jongejan, Aldo

Transducin β-like 1 X-linked receptor 1 (mouse Tbl1xr1) or TBL1X/Y related 1 (human TBL1XR1), part of the NCoR/SMRT corepressor complex, is involved in nuclear receptor signaling. Variants in TBL1XR1 cause a variety of neurodevelopmental disorders including Pierpont syndrome caused by the p.Tyr446Cys variant. We recently reported a mouse model carrying the Tbl1xr1^Y446C/Y446C variant as a model for Pierpont syndrome. To obtain insight into mechanisms involved in altered brain development we studied gene expression patterns in the cortex of mutant and wild type (WT) mice, using RNA-sequencing, differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene correlation network analysis (WGCNA) and hub gene analysis. We validated results in mutated mouse cortex, as well as in BV2 and SK-N-AS cell lines, in both of which Tbl1xr1 was knocked down by siRNA. Two DEGs (adj.P. Val < 0.05) were found in the cortex, Mpeg1 (downregulated in mutant mice) and 2900052N01Rik (upregulated in mutant mice). GSEA, WGCNA and hub gene analysis demonstrated changes in genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1^Y446C/Y446C mice. The lowered expression of ion channel genes Kcnh3 and Kcnj4 mRNA was validated in the mutant mouse cortex, and increased expression of TRIM9, associated with neuroinflammation, was confirmed in the SK-N-AS cell line. Conclusively, our results show altered expression of genes involved in ion channel function and neuroinflammation in the cortex of the Tbl1xr1^Y446C/Y446C mice. These may partly explain the impaired neurodevelopment observed in individuals with Pierpont syndrome and related TBL1XR1-related disorders.

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