The scaffold protein Transducin Beta-Like 1X-Linked (TBL1X) functions as an essential component in cell signal transduction and gene transcription regulation while participating in chromatin remodeling and protein homeostasis maintenance. Through its role in multiple protein complexes it controls cellular physiological functions. The protein TBL1X (Transducin Beta-Like 1X-Linked) serves to link chromatin remodeling processes with mechanisms that regulate gene expression. TBL1X plays essential roles in Wnt/β-catenin signaling and the regulation of nuclear receptor complexes while participating in the ubiquitin-proteasome system.
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Structure and Function of TBL1X
TBL1X functions as a scaffold protein within the WD40 domain protein family because its WD40 repeat sequence allows it to assemble and regulate multiple protein complexes. Its main physiological activities include:
- Chromatin remodeling and gene transcription regulation
- Wnt/β-catenin signaling pathway regulation
- Ubiquitin-mediated protein degradation
- Metabolic homeostasis regulation
- Immune regulation
Role of TBL1X in Physiological Processes
Participates in Gene Transcription Regulation
TBL1X forms a part of the NCoR/SMRT complex which inhibits nuclear receptor activity together with other transcription factors.
Coactivation and Co-inhibition
TBL1X activates specific gene transcription through the promotion of NCoR/SMRT complex dissociation. In different scenarios TBL1X functions as a co-repressor which assists in the recruitment of histone deacetylases (HDACs) to block target gene expression.
Regulates Glucose Metabolism and Lipid Metabolism
TBL1X regulates lipid metabolism and insulin signaling pathways through its influence on PPARγ and LXR activities.
Promotes Wnt/β-catenin Signaling Pathway
Through its regulation of β-catenin stability TBL1X triggers the activation of the Wnt signaling pathway. TBL1X functions to stabilize β-catenin and stops its degradation. The protein TBL1X helps β-catenin migrate to the nucleus where it binds TCF/LEF transcription factors to stimulate cell growth and differentiation and activate embryonic-developmental genes. The Wnt signaling pathway depends on TBL1X for crucial functions in neural development as well as bone formation and intestinal homeostasis.
Participates in Ubiquitin-mediated Protein Degradation
The protein TBL1X functions in the ubiquitin-proteasome system (UPS) to control the breakdown of particular transcription factors including the degradation of tumor suppressor proteins p53 and FoxO1 which impacts the regulation of the cell cycle and metabolism. TBL1X protects nuclear receptors and β-catenin from degradation to influence gene expression patterns and cell signaling pathways.
Maintains Metabolic Homeostasis
TBL1X regulates energy metabolism through its impact on adipocyte differentiation and lipid storage functions. Blood glucose homeostasis operates through the regulation of insulin sensitivity and gluconeogenesis pathways.
Physiological and Pathological Relevance of TBL1X
TBL1X participates in multiple pathological processes which span across cancer development and metabolic and neurological diseases.
Cancer: TBL1X overexpression enhances Wnt/β-catenin signaling thereby speeding up cancer cell growth in contexts like colorectal and liver cancer.
Metabolic diseases: The abnormal expression of TBL1X which influences fat and sugar metabolism can lead to obesity and diabetes development.
Neurological diseases: Mutations in TBL1X lead to X-linked intellectual disability (XLID) while also impacting neural development and synaptic plasticity.
TBL1X Induces Cancer Through Changes at The Level of Gene Transcription
TBL1X influences gene transcription by controlling the nuclear receptor coactivator complex (NCoR/SMRT) and manipulating the Wnt/β-catenin signaling pathway. TBL1X acts as a coactivator of β-catenin which helps β-catenin move into the nucleus to attach to TCF/LEF complex and activate cancer-related genes including c-Myc and Cyclin D1. The Wnt signaling pathway's abnormal activation functions as a primary contributor to several cancers including colorectal cancer, liver cancer, and breast cancer. Through β-catenin stabilization TBL1X enables cancer cells to proliferate and survive.
TBL1X engages in HDAC complex remodeling while promoting NCoR/SMRT transcriptional co-repressor dissociation which allows transcription factors like STAT3 and NF-κB to activate oncogenes. The activity strengthens inflammation-related pathways specifically the IL-6/STAT3 axis which leads to enhanced cancer cell survival and evasion from the immune system. By participating in the ubiquitin-proteasome system (UPS), TBL1X regulates the breakdown of key transcription factors including p53 and FoxO1 which disrupts tumor suppressor signal pathways.
Fig 1 . Schematic representation of the broad multifunctionality of transducin beta-like protein 1 (TBL1X) (Pray, B., et al. 2022).
TBL1X as a Potential Anticancer Target
TBL1X serves as a potential therapeutic target due to its crucial function in cancer progression. Possible treatment strategies include:
Wnt/β-catenin inhibitors: TBL1X treatment targets embrace both Tankyrase inhibitors like XAV939 and β-catenin blockers such as PRI-724.
Treatment strategies should focus on miRNA-based regulatory networks to rehabilitate tumor suppressor miRNAs like miR-34 and miR-200.
Small molecule inhibitors along with siRNA suppress TBL1X expression to diminish its cancer-promoting ability in cancer cells.
Carcinogenic Role of TBL1X in Post-transcriptional Regulation
TBL1X influences tumor progression by RNA binding as well as mRNA stability regulation and non-coding RNA interaction besides its direct impact on gene transcription.
TBL1X modifies RNA binding protein stability which lengthens the half-life of oncogene mRNA and boosts protein production. In select cancer types TBL1X disrupts mRNA degradation routes like the CCR4-NOT complex which leads to sustained oncogene expression.
The activity of TBL1X involves interaction with particular microRNAs (miRNAs) to modulate miRNA-mediated mRNA degradation processes. The suppression of tumor suppressor miRNAs (like miR-34 and miR-200) leads to the release of oncogene inhibition. Enhance oncogene expression by boosting tumor-promoting miRNAs like miR-21 and miR-155. Research revealed that specific long noncoding RNAs (lncRNAs) influence post-transcriptional control of cancer-related genes through TBL1X expression regulation or by forming complexes with TBL1X.
TBL1X stimulates cancer cell growth and survival while helping cancer evade the immune system through transcriptional and post-transcriptional regulatory mechanisms. Research into how TBL1X functions and how it can be targeted in cancer therapy may lead to new strategies for developing future cancer drugs.
References
- Pray, B., et al. TBL1X: At the crossroads of transcriptional and posttranscriptional regulation. Experimental hematology. 2022, 116: 18-25.
- Hurwitz, S., et al. TBL1 Inhibition Eradicates Drug Resistant Leukemia Initiating Cells in T-ALL." Blood 144 (2024): 1418.
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