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Target: TUBB


Research on the Target TUBB

1. Target Summary:

TUBB, or tubulin beta chain, is a critical component of microtubules, which are essential for various cellular functions, including maintaining cell shape, intracellular transport, and cell division. TUBB is part of the tubulin family, which consists of alpha and beta subunits that polymerize to form microtubules. Mutations and variations in TUBB have been linked to several diseases, including neurodevelopmental disorders and various cancers.

2. Mechanism:

TUBB functions by polymerizing with alpha-tubulin to form heterodimers, which then assemble into microtubules. These microtubules are dynamic structures that undergo constant remodeling, playing a vital role in mitosis, intracellular transport, and maintaining cell structure. The binding of GTP to TUBB is crucial for microtubule stability; hydrolysis of GTP to GDP leads to microtubule destabilization, which can trigger depolymerization.
In cancer therapy, TUBB is targeted by various drugs that either stabilize or destabilize microtubules. For instance, agents like paclitaxel stabilize microtubules, preventing their disassembly, while others like rigosertib destabilize them, leading to cell death. The specificity of TUBB for these agents can be influenced by mutations in the TUBB gene, which can alter the binding sites for these drugs (Jost et al., 2020; PMID: 32619469).

3. Approved Drugs:

Several drugs target TUBB, including:
  • Paclitaxel: A microtubule stabilizer used in various cancers.
  • Rigosertib: A microtubule-destabilizing agent currently in clinical trials.
  • ABT-751: An oral antimitotic agent that binds to the colchicine site on beta-tubulin, currently undergoing clinical evaluation (Yee et al., 2005; PMID: 16166440).

4. Hypotheses:

  1. TUBB Mutations and Disease: Variants in the TUBB gene may lead to neurodevelopmental disorders due to disrupted microtubule dynamics, resulting in conditions such as lissencephaly and microcephaly.
  2. Cancer Progression: Alterations in TUBB expression levels may correlate with tumor progression and patient prognosis, suggesting that TUBB could serve as a biomarker for cancer outcomes.
  3. Therapeutic Targeting: Targeting TUBB with specific inhibitors could provide a novel therapeutic approach in treating cancers with high TUBB expression or specific mutations.

5. Validation:

The role of TUBB in disease has been validated through various studies linking its mutations to specific phenotypes in neurodevelopmental disorders and its expression levels to cancer prognosis. For instance, studies have shown that mutations in TUBB are associated with cortical malformations (Tantry et al., 2023; PMID: 36943622). Additionally, TUBB's expression has been correlated with clinical features in various cancers, supporting its role as a potential biomarker (Zhu et al., 2024; PMID: 38756529).

6. Clinical Trials:

  • Rigosertib: Currently in phase III clinical trials for various cancers, demonstrating efficacy by destabilizing microtubules (Jost et al., 2020; PMID: 32619469).
  • ABT-751: A phase 1 study has been conducted to evaluate its safety and efficacy in patients with refractory hematologic malignancies (Yee et al., 2005; PMID: 16166440).

7. Involved Pathways:

TUBB is involved in several cellular pathways, including:
  • Cell Cycle Regulation: Microtubules play a crucial role in mitosis, and TUBB is essential for proper spindle formation.
  • Intracellular Transport: Microtubules serve as tracks for the transport of organelles and vesicles within cells.
  • Signal Transduction: Microtubules are involved in signaling pathways that regulate cell growth and differentiation.

8. Associated Genes:

  • TUBB: The primary gene encoding the beta-tubulin protein.
  • TUBA: The gene encoding alpha-tubulin, which heterodimerizes with TUBB to form microtubules.
  • TUBB3: A variant of TUBB associated with specific neurological disorders.

9. Target Expression:

TUBB is expressed in various tissues, with higher expression levels observed in rapidly dividing cells, such as those found in tumors. Its expression can be influenced by factors such as hypoxia and cellular stress, which may alter microtubule dynamics and stability.

10. Additional Context:

TUBB's role extends beyond structural functions; it is also involved in cellular signaling and the regulation of apoptosis. The study of TUBB and its variants is crucial for understanding the underlying mechanisms of various diseases and developing targeted therapies.

11. References:

  • Jost, M., Chen, Y., & Gilbert, L. A. (2020). Pharmaceutical-Grade Rigosertib Is a Microtubule-Destabilizing Agent. Molecular Cell, 78(1), 1-12. PMID: 32619469
  • Yee, K. W., Hagey, A., & Verstovsek, S. (2005). Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies. Clinical Cancer Research, 11(18), 6595-6601. PMID: 16166440
  • Tantry, M. S. A., & Santhakumar, K. (2023). Insights on the Role of alpha- and beta-Tubulin Isotypes in Early Brain Development. Molecular Neurobiology. PMID: 36943622
  • Zhu, Z., Zhang, W., & Huo, S. (2024). TUBB, a robust biomarker with satisfying abilities in diagnosis, prognosis, and immune regulation via a comprehensive pan-cancer analysis. Frontiers in Molecular Biosciences. PMID: 38756529
This comprehensive overview provides insights into the significance of TUBB in health and disease, highlighting its potential as a therapeutic target and biomarker in various conditions.