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Biology:Class III β-tubulin

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Short description: Microtubule element of the tubulin family

Template:Cs1 config Class III β-tubulin, otherwise known as βIII-tubulin (β3-tubulin) or β-tubulin III, is a microtubule element of the tubulin family found almost exclusively in neurons,[1][2] and in testis cells.[3][4] In humans, it is encoded by the TUBB3 gene.[5][6][7][3][8][9]

Forebrain neuronal culture after 40 days of differentiation from induced human pluripotent stem cells. iPSCs from a patient with familial Alzheimer's disease, a mutation in the PSEN1 gene. TUJ-1-positive cells express a marker (β3-tubulin) of mature neurons (red). GABA-positive cells (green). Cell nuclei are stained with DAPI (blue).

It is possible to use monoclonal antibodies and immunohistochemistry to identify neurons in samples of brain tissue, separating neurons from glial cells, which do not express Class III β-tubulin.

Class III β-tubulin is one of the seven β-tubulin isotypes identified in the human genome, predominantly in neurons and the testis. It is conditionally expressed in a number of other tissues after exposure to a toxic microenvironment featured by hypoxia and poor nutrient supply.[10][11][12] Posttranslational changes including phosphorylation and glycosylation are required for functional activity.[8] Class III β-tubulin's role in neural development has warranted its use as an early biomarker of neural cell differentiation from multi potent progenitors.[13] TUBB3 inactivation impairs neural progenitor proliferation. Rescue experiments demonstrate the non-interchangeability of TUBB3 with other classes of β-tubulins which cannot restore the phenotype resulting from TUBB3 inactivation.[14] Congenital neurologic syndromes associated with TUBB3 missense mutations demonstrate the critical importance of class III β-tubulin for normal neural development.[9][15]

Gene

The human TUBB3 gene is located on chromosome 16q24.3, and consists of 4 exons that transcribe a protein of 450aa. A shorter isoform of 378aa derived from alternative splicing of exon 1 is devoid of part of the N-terminus and may be responsible for mitochondrial expression.[8][16] Like other β-tubulin isotypes, βIII-tubulin has a GTPase domain which plays an essential role in regulating microtubule dynamics.[17] Differences between Class I (the most commonly represented and constitutively expressed isotype) and class III β-tubulin are limited to only 13aa within region 1-429aa, while all amino acids in region 430-450aa are divergent. These variations in primary structure affect the paclitaxel (a mimic of Nur77) binding domain on βIII-tubulin and may account for the ability of this isotype to confer resistance to Nur77-initiated apoptosis.[18]

Function

Cysteine residues in class III β-tubulin are actively involved in regulating ligand interactions and microtubule formation. Proteomic analysis has revealed that many factors bound to these cysteine residues are involved in the oxidative stress and glucose deprivation response.[8] This is particularly interesting in light of the fact that class III β-tubulin first appears in the phylogenetic tree when life emerged from the seas and cells were exposed to atmospheric oxygen.[19] In structural terms, constitutive Class I (TUBB) and Class IVb (TUBB2C) β-tubulins contain a cysteine at position 239, while βIII-tubulin has a cysteine at position 124. Position 239 can be readily oxidized while position 124 is relatively resistant to oxidation.[20] Thus, a relative abundance of βIII-tubulin in situations of oxidative stress could provide a protective benefit.

Interactions

The interactome of class III β-tubulin comprises the GTPase GBP1 (guanylate binding protein 1) and a panel of an additional 19 kinases having prosurvival activity including PIM1 (Proviral Integration Site 1) and NEK6 (NIMA-related kinase 6). Incorporation of these kinases into the cytoskeleton via the GBP-1/ class III β-tubulin interaction protects kinases from rapid degradation.[21] Other pro-survival factors interacting with class III β-tubulin enabling cellular adaptation to oxidative stress include the molecular chaperone HSP70/GRP75.[22] FMO4 (vimentin/dimethylalanine monooxygenase 4) and GSTM4 (glutathione transferase M4).[8]

Regulation

The expression of Class III β-tubulin is regulated at both the transcriptional and translational levels. In neural tissue, constitutive expression is driven by Sox4 and Sox11.[23] In non-neural tissues, regulation is dependent on an E-box site in the 3' flanking region at +168 nucleotides. This site binds basic helix-loop-helix (bHLH) hypoxia induced transcription factors Hif-1α and Hif-2α and is epigenetically modified in cancer cells with constitutive TUBB3 expression.[10][24] Translational regulation of TUBB3 occurs in the 3`flanking region with the interaction of the miR-200c family of micro-RNA.[25][26] MiR-200c is in turn modulated by the protein HuR (encoded by ELAVL1). When HuR is predominantly in the nucleus, a phenomenon typically occurring in low stage carcinomas, miR-200c suppresses class III β-tubulin translation. By contrast, cytoplasmic HuR and miR-200c enhance class III β-tubulin translation by facilitating the entry of the mRNA into the ribosome.[11][27]

Role in cancer

In oncology, class III β-tubulin has been investigated as both a prognostic biomarker and an indicator of resistance to taxanes and other compounds.[28][29] The majority of reports implicate class III β-tubulin as a biomarker of poor outcome. However, there are also data in clear cell carcinoma, melanoma and breast cancer showing favorable prognosis.[30][31][32][33] Class III β-tubulin is integral component of a pro-survival, cascading molecular pathway which renders cancer cells resistant to apoptosis and enhances their ability to invade local tissues and metastasize.[10][34][35][36] Class III β-tubulin performs best as a prognostic biomarker when analyzed in the context of an integrated signature including upstream regulators and downstream effectors.[11][27][37] TUBB3 mutation is associated with microlissencephaly.

Overexpression of this isotype in clinical samples correlates with tumor aggressiveness, resistance to chemotherapeutic drugs, and poor patient survival.[38][39]

Pathophysiology

The β3 isotype increases tumor aggressiveness by two distinct mechanisms. Incorporation of this isotype makes microtubule networks hypostable, allowing them to resist the cytotoxic effects of microtubule stabilizing drugs like taxanes or epothilones. Mechanistically, it was found that overexpression of β3-tubulin increases the rate of microtubule detachment from microtubule organizing centers, an activity that is suppressed by drugs such as paclitaxel.[40]

Expression of β3-tubulin also makes cells more aggressive by altering their response to drug-induced suppression of microtubule dynamics.[41] Dynamic microtubules are needed for the cell migration that underlies processes such as tumor metastasis and angiogenesis. The dynamics are normally suppressed by low, subtoxic concentrations of microtubule drugs that also inhibit cell migration. However, incorporating β3-tubulin into microtubules increases the concentration of drug that is needed to suppress dynamics and inhibit cell migration. Thus, tumors that express β3-tubulin are not only resistant to the cytotoxic effects of microtubule targeted drugs, but also to their ability to suppress tumor metastasis. Moreover, expression of β3-tubulin also counteracts the ability of these drugs to inhibit angiogenesis which is normally another important facet of their action.

Notes

References

  1. ↑ "Identification of conserved isotype-defining variable region sequences for four vertebrate beta tubulin polypeptide classes.". Proceedings of the National Academy of Sciences of the United States of America 83 (12): 4327–31. June 1986. doi:10.1073/pnas.83.12.4327. PMID 3459176. Bibcode: 1986PNAS...83.4327S. 
  2. ↑ "An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated beta-tubulin isotype.". The American Journal of Pathology 135 (5): 801–13. November 1989. PMID 2817080. 
  3. ↑ 3.0 3.1 "Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work?". Current Cancer Drug Targets 7 (8): 704–12. December 2007. doi:10.2174/156800907783220453. PMID 18220531. 
  4. ↑ "Expression of Tubb3, a beta-tubulin isotype, is regulated by androgens in mouse and rat Sertoli cells.". Biology of Reproduction 85 (5): 934–45. November 2011. doi:10.1095/biolreprod.110.090704. PMID 21734264. 
  5. ↑ "Cloning and sequencing of human betaIII-tubulin cDNA: induction of betaIII isotype in human prostate carcinoma cells by acute exposure to antimicrotubule agents". Biochim Biophys Acta 1395 (2): 237–45. Mar 1998. doi:10.1016/s0167-4781(97)00168-1. PMID 9473684. 
  6. ↑ "Identification of new human receptor and transporter genes by high throughput cDNA (EST) sequencing". J Pharm Pharmacol. 45 Suppl 1: 355–60. Jun 1993. PMID 8098743. 
  7. ↑ "Entrez Gene: TUBB3 tubulin, beta 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10381. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Proteomic characterization of cytoskeletal and mitochondrial class III beta-tubulin.". Molecular Cancer Therapeutics 7 (7): 2070–9. July 2008. doi:10.1158/1535-7163.mct-07-2370. PMID 18645017. https://aacr.figshare.com/articles/journal_contribution/Supplementary_Fig_from_Proteomic_characterization_of_cytoskeletal_and_mitochondrial_class_III_-tubulin/22483856/1/files/39935390.pdf. 
  9. ↑ 9.0 9.1 "Mutations in the neuronal ß-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects.". Human Molecular Genetics 19 (22): 4462–73. 15 November 2010. doi:10.1093/hmg/ddq377. PMID 20829227. 
  10. ↑ 10.0 10.1 10.2 "Hypoxia induces class III beta-tubulin gene expression by HIF-1alpha binding to its 3' flanking region.". Gene 409 (1–2): 100–8. 15 February 2008. doi:10.1016/j.gene.2007.11.015. PMID 18178340. 
  11. ↑ 11.0 11.1 11.2 "HuR regulates beta-tubulin isotype expression in ovarian cancer.". Cancer Research 70 (14): 5891–900. 15 July 2010. doi:10.1158/0008-5472.can-09-4656. PMID 20587520. 
  12. ↑ "Aberrant localization of the neuronal class III beta-tubulin in astrocytomas.". Archives of Pathology & Laboratory Medicine 125 (5): 613–24. May 2001. doi:10.5858/2001-125-0613-ALOTNC. PMID 11300931. 
  13. ↑ "Characterization of epidermal neural crest stem cell (EPI-NCSC) grafts in the lesioned spinal cord.". Molecular and Cellular Neurosciences 32 (1–2): 67–81. 2006. doi:10.1016/j.mcn.2006.02.003. PMID 16626970. 
  14. ↑ "Beta tubulin isoforms are not interchangeable for rescuing impaired radial migration due to Tubb3 knockdown.". Human Molecular Genetics 23 (6): 1516–26. 15 March 2014. doi:10.1093/hmg/ddt538. PMID 24179174. 
  15. ↑ "Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.". Cell 140 (1): 74–87. 8 January 2010. doi:10.1016/j.cell.2009.12.011. PMID 20074521. 
  16. ↑ "Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells'.". Cancer Research 60 (19): 5349–53. 1 October 2000. PMID 11034069. 
  17. ↑ "Tubulins as therapeutic targets in cancer: from bench to bedside.". Current Pharmaceutical Design 18 (19): 2778–92. 2012. doi:10.2174/138161212800626193. PMID 22390762. 
  18. ↑ "Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77.". Cancer Research 69 (17): 6906–14. 1 September 2009. doi:10.1158/0008-5472.can-09-0540. PMID 19671798. 
  19. ↑ "The evolution of the structure of tubulin and its potential consequences for the role and function of microtubules in cells and embryos.". The International Journal of Developmental Biology 50 (2–3): 341–58. 2006. doi:10.1387/ijdb.052063jt. PMID 16479502. 
  20. ↑ "The roles of cys124 and ser239 in the functional properties of human betaIII tubulin.". Cell Motility and the Cytoskeleton 65 (6): 476–86. June 2008. doi:10.1002/cm.20274. PMID 18435451. 
  21. ↑ "Class III β-tubulin and the cytoskeletal gateway for drug resistance in ovarian cancer.". Journal of Cellular Physiology 227 (3): 1034–41. March 2012. doi:10.1002/jcp.22813. PMID 21520077. 
  22. ↑ "Identification of proteins binding the native tubulin dimer.". Biochemical and Biophysical Research Communications 327 (1): 35–42. 4 February 2005. doi:10.1016/j.bbrc.2004.11.138. PMID 15629426. 
  23. ↑ "The establishment of neuronal properties is controlled by Sox4 and Sox11.". Genes & Development 20 (24): 3475–86. 15 December 2006. doi:10.1101/gad.403406. PMID 17182872. 
  24. ↑ "Molecular mechanisms of patupilone resistance.". Cancer Research 68 (24): 10197–204. 15 December 2008. doi:10.1158/0008-5472.can-08-2091. PMID 19074887. 
  25. ↑ "MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents.". Molecular Cancer Therapeutics 8 (5): 1055–66. May 2009. doi:10.1158/1535-7163.mct-08-1046. PMID 19435871. 
  26. ↑ "Loss of miR-200c: A Marker of Aggressiveness and Chemoresistance in Female Reproductive Cancers.". Journal of Oncology 2010: 821717. 2010. doi:10.1155/2010/821717. PMID 20049172. 
  27. ↑ 27.0 27.1 "MiR-200c and HuR in ovarian cancer.". BMC Cancer 13: 72. 8 February 2013. doi:10.1186/1471-2407-13-72. PMID 23394580. 
  28. ↑ "Class III β-tubulin (TUBB3): more than a biomarker in solid tumors?". Current Molecular Medicine 11 (9): 726–31. December 2011. doi:10.2174/156652411798062368. PMID 21999149. 
  29. ↑ "βIII-Tubulin: biomarker of taxane resistance or drug target?". Expert Opinion on Therapeutic Targets 17 (4): 461–72. April 2013. doi:10.1517/14728222.2013.766170. PMID 23379899. 
  30. ↑ "Overexpression of class III beta-tubulin predicts good response to taxane-based chemotherapy in ovarian clear cell adenocarcinoma.". Clinical Cancer Research 15 (4): 1473–80. 15 February 2009. doi:10.1158/1078-0432.ccr-08-1274. PMID 19228748. 
  31. ↑ "Class III beta-tubulin isotype predicts response in advanced breast cancer patients randomly treated either with single-agent doxorubicin or docetaxel.". Clinical Cancer Research 14 (14): 4511–6. 15 July 2008. doi:10.1158/1078-0432.ccr-07-4741. PMID 18628466. 
  32. ↑ "High expression of class III β-tubulin predicts good response to neoadjuvant taxane and doxorubicin/cyclophosphamide-based chemotherapy in estrogen receptor-negative breast cancer.". Clinical Breast Cancer 13 (2): 103–8. April 2013. doi:10.1016/j.clbc.2012.11.003. PMID 23218766. 
  33. ↑ "Loss of class III beta-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells.". The Journal of Investigative Dermatology 129 (6): 1516–26. June 2009. doi:10.1038/jid.2008.406. PMID 19122647. 
  34. ↑ "Class III beta-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer.". Cancer Research 67 (19): 9356–63. 1 October 2007. doi:10.1158/0008-5472.can-07-0509. PMID 17909044. 
  35. ↑ "betaIII-tubulin is a multifunctional protein involved in drug sensitivity and tumorigenesis in non-small cell lung cancer.". Cancer Research 70 (12): 4995–5003. 15 June 2010. doi:10.1158/0008-5472.can-09-4487. PMID 20501838. 
  36. ↑ "TUBB3/βIII-Tubulin Acts through the PTEN/AKT Signaling Axis to Promote Tumorigenesis and Anoikis Resistance in Non-Small Cell Lung Cancer.". Cancer Research 75 (2): 415–25. 20 November 2014. doi:10.1158/0008-5472.CAN-14-2740. PMID 25414139. 
  37. ↑ "Sox9 and Hif-2α regulate TUBB3 gene expression and affect ovarian cancer aggressiveness.". Gene 542 (2): 173–81. 1 June 2014. doi:10.1016/j.gene.2014.03.037. PMID 24661907. 
  38. ↑ Karki, R; Marini, M; Andreoli, M; He, S; Scambia, G; Shahabi, S; Ferlini, C (2013). "βIII-Tubulin: biomarker of taxane resistance or drug target?". Expert Opin Ther Targets 17 (4): 461–72. doi:10.1517/14728222.2013.766170. PMID 23379899. 
  39. ↑ Ferrandina, G; Zannoni, GF; Martinelli, E; Paglia, A; Gallotta, V; Mozzetti, S; Scambia, G; Ferlini, C (2006). "Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients.". Clin. Cancer Res. 12 (9): 2774–9. doi:10.1158/1078-0432.CCR-05-2715. PMID 16675570. 
  40. ↑ Ganguly, A; Cabral, F (2011). "New insights into mechanisms of resistance to microtubule inhibitors". Biochim Biophys Acta 1816 (2): 2774–9. doi:10.1016/j.bbcan.2011.06.001. PMID 21741453. 
  41. ↑ Ganguly, A; Yang, H; Cabral, F (2011). "Class III β-tubulin counteracts the ability of paclitaxel to inhibit cell migration.". Oncotarget 2 (5): 368–377. doi:10.18632/oncotarget.250. PMID 21576762. 



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