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Target: TUBB4B


Research on TUBB4B

1. Target Summary:

TUBB4B (Tubulin Beta 4B) is a gene located on chromosome 9q34.3 that encodes the beta-4B tubulin isotype, a crucial component of microtubules. Microtubules are essential for various cellular processes, including maintaining cell shape, intracellular transport, and cell division. Mutations in TUBB4B are associated with several diseases, including inherited retinal dystrophy (IRD), sensorineural hearing loss (SNHL), and various forms of tubulinopathies. TUBB4B is also recognized as a novel therapeutic target in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) (Yang et al., 2023).

2. Mechanism:

TUBB4B functions primarily by forming heterodimers with alpha-tubulin to create microtubules, which are integral to the cytoskeleton. The stability and dynamics of microtubules are influenced by the specific isotypes of tubulin, including TUBB4B. Mutations in TUBB4B can lead to structural instability in microtubules, affecting cellular processes such as mitosis, intracellular transport, and the maintenance of cell shape.
In the context of diseases, TUBB4B mutations can disrupt microtubule dynamics, leading to cellular dysfunction. For example, in cochlear supporting cells, TUBB4B is essential for the architecture of microtubules, and its absence results in hearing loss due to disorganized microtubules (Sanzhaeva et al., 2024). Additionally, TUBB4B has been implicated in liver fibrosis through the IGF2BP1/TUBB4B/FAK signaling axis, where it contributes to the activation of hepatic stellate cells (Li et al., 2024).

3. Approved Drugs:

Currently, mebendazole (MBZ), an FDA-approved drug, has been identified as a potential inhibitor of TUBB4B. It has shown efficacy in inhibiting the growth of NAFLD-HCC cells by inducing apoptosis and cellular senescence (Yang et al., 2023). However, further clinical validation is needed to establish its effectiveness specifically targeting TUBB4B.

4. Hypotheses:

  1. Microtubule Instability Hypothesis: Mutations in TUBB4B lead to microtubule instability, resulting in cellular dysfunction and contributing to the pathogenesis of associated diseases such as IRD and SNHL (Bodenbender et al., 2024).
  2. Therapeutic Target Hypothesis: Targeting TUBB4B with inhibitors like mebendazole may provide therapeutic benefits in cancers such as NAFLD-HCC by inducing apoptosis and inhibiting tumor growth (Yang et al., 2023).
  3. Compensatory Mechanism Hypothesis: In the absence of TUBB4B, other tubulin isotypes may compensate for its function, which could influence the severity of phenotypes associated with TUBB4B mutations (Sanzhaeva et al., 2024).

5. Validation:

The association of TUBB4B mutations with specific diseases has been validated through genetic studies and functional assays. For instance, patients with mutations at codons Arg390 and Arg391 exhibit distinct phenotypes of IRD and SNHL, supporting the role of TUBB4B in these conditions (Bodenbender et al., 2024). Additionally, the efficacy of mebendazole in inhibiting NAFLD-HCC growth provides preliminary validation for TUBB4B as a therapeutic target (Yang et al., 2023).

6. Clinical Trials:

As of now, there are no specific clinical trials targeting TUBB4B directly. However, ongoing research into the use of mebendazole and other agents targeting microtubule dynamics in cancer treatment may provide insights into potential clinical applications for TUBB4B.

7. Involved Pathways:

TUBB4B is involved in several cellular pathways, including:
  • Microtubule Dynamics: Essential for cell shape, division, and intracellular transport.
  • IGF2BP1/TUBB4B/FAK Signaling: Implicated in liver fibrosis and the activation of hepatic stellate cells (Li et al., 2024).
  • ERK Signaling Pathway: TUBB4B expression is regulated by AGTPBP1, which is involved in pancreatic cancer progression (Li et al., 2024).

8. Associated Genes:

  • AGTPBP1: Regulates TUBB4B expression and is implicated in pancreatic cancer (Li et al., 2024).
  • IGF2BP1: Stabilizes TUBB4B mRNA and is involved in liver fibrosis (Li et al., 2024).
  • Alpha-tubulin genes: Interact with TUBB4B to form microtubules.

9. Target Expression:

TUBB4B is expressed in various tissues, with significant roles in the brain, cochlea, and liver. Its expression levels can vary in different pathological conditions, such as being overexpressed in NAFLD-HCC tumors compared to adjacent normal tissues (Yang et al., 2023).

10. Additional Context:

TUBB4B mutations have been linked to a spectrum of disorders, including tubulinopathies characterized by cerebral malformations and sensory deficits. Understanding the specific roles of TUBB4B in these conditions can aid in developing targeted therapies and improving patient outcomes.

11. References:

  • Bodenbender JP, Marino V, Philipp J. Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes. Scientific Reports. 2024; PMID: 38719929.
  • Li Y, Chen L, Li S. The m6A reader IGF2BP1 contributes to the activation of hepatic stellate cells through facilitating TUBB4B mRNA stabilization. Journal of Gastroenterology and Hepatology. 2024; PMID: 39403946.
  • Sanzhaeva U, Boyd-Pratt H, Bender PTR. TUBB4B is essential for the cytoskeletal architecture of cochlear supporting cells and motile cilia development. Communications Biology. 2024; PMID: 39277687.
  • Yang Z, Gao S, Wong CC. TUBB4B is a novel therapeutic target in non-alcoholic fatty liver disease-associated hepatocellular carcinoma. The Journal of Pathology. 2023; PMID: 36787097.