Class III β-tubulin

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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]

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.

References

  1. ↑ Sullivan KF, Cleveland DW (June 1986). "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. doi:10.1073/pnas.83.12.4327. PMC 323725. PMID 3459176.
  2. ↑ Caccamo DV, Herman MM, Frankfurter A, Katsetos CD, Collins VP, Rubinstein LJ (November 1989). "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. PMC 1880094. PMID 2817080.
  3. ↑ 3.0 3.1 Ferlini C, Raspaglio G, Cicchillitti L, Mozzetti S, Prislei S, Bartollino S, Scambia G (December 2007). "Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work?". Current Cancer Drug Targets. 7 (8): 704–12. doi:10.2174/156800907783220453. PMID 18220531.
  4. ↑ De Gendt K, Denolet E, Willems A, Daniels VW, Clinckemalie L, Denayer S, Wilkinson MF, Claessens F, Swinnen JV, Verhoeven G (November 2011). "Expression of Tubb3, a beta-tubulin isotype, is regulated by androgens in mouse and rat Sertoli cells". Biology of Reproduction. 85 (5): 934–45. doi:10.1095/biolreprod.110.090704. PMC 4480425. PMID 21734264.
  5. ↑ Ranganathan S, Dexter DW, Benetatos CA, Hudes GR (Mar 1998). "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. doi:10.1016/s0167-4781(97)00168-1. PMID 9473684.
  6. ↑ Venter JC (Jun 1993). "Identification of new human receptor and transporter genes by high throughput cDNA (EST) sequencing". J Pharm Pharmacol. 45. Suppl 1: 355–60. PMID 8098743.
  7. ↑ "Entrez Gene: TUBB3 tubulin, beta 3".
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Cicchillitti L, Penci R, Di Michele M, Filippetti F, Rotilio D, Donati MB, Scambia G, Ferlini C (July 2008). "Proteomic characterization of cytoskeletal and mitochondrial class III beta-tubulin". Molecular Cancer Therapeutics. 7 (7): 2070–9. doi:10.1158/1535-7163.mct-07-2370. PMID 18645017.
  9. ↑ 9.0 9.1 Poirier K, Saillour Y, Bahi-Buisson N, Jaglin XH, Fallet-Bianco C, Nabbout R, Castelnau-Ptakhine L, Roubertie A, Attie-Bitach T, Desguerre I, Genevieve D, Barnerias C, Keren B, Lebrun N, Boddaert N, Encha-Razavi F, Chelly J (15 November 2010). "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. doi:10.1093/hmg/ddq377. PMC 3298850. PMID 20829227.
  10. ↑ 10.0 10.1 10.2 Raspaglio G, Filippetti F, Prislei S, Penci R, De Maria I, Cicchillitti L, Mozzetti S, Scambia G, Ferlini C (15 February 2008). "Hypoxia induces class III beta-tubulin gene expression by HIF-1alpha binding to its 3' flanking region". Gene. 409 (1–2): 100–8. doi:10.1016/j.gene.2007.11.015. PMID 18178340.
  11. ↑ 11.0 11.1 11.2 Raspaglio G, De Maria I, Filippetti F, Martinelli E, Zannoni GF, Prislei S, Ferrandina G, Shahabi S, Scambia G, Ferlini C (15 July 2010). "HuR regulates beta-tubulin isotype expression in ovarian cancer". Cancer Research. 70 (14): 5891–900. doi:10.1158/0008-5472.can-09-4656. PMID 20587520.
  12. ↑ Katsetos CD, Del Valle L, Geddes JF, Assimakopoulou M, Legido A, Boyd JC, Balin B, Parikh NA, Maraziotis T, de Chadarevian JP, Varakis JN, Matsas R, Spano A, Frankfurter A, Herman MM, Khalili K (May 2001). "Aberrant localization of the neuronal class III beta-tubulin in astrocytomas". Archives of Pathology & Laboratory Medicine. 125 (5): 613–24. doi:10.1043/0003-9985(2001)125<0613:ALOTNC>2.0.CO;2. PMID 11300931.
  13. ↑ Sieber-Blum M, Schnell L, Grim M, Hu YF, Schneider R, Schwab ME (2006). "Characterization of epidermal neural crest stem cell (EPI-NCSC) grafts in the lesioned spinal cord". Molecular and Cellular Neurosciences. 32 (1–2): 67–81. doi:10.1016/j.mcn.2006.02.003. PMID 16626970.
  14. ↑ Saillour Y, Broix L, Bruel-Jungerman E, Lebrun N, Muraca G, Rucci J, Poirier K, Belvindrah R, Francis F, Chelly J (15 March 2014). "Beta tubulin isoforms are not interchangeable for rescuing impaired radial migration due to Tubb3 knockdown". Human Molecular Genetics. 23 (6): 1516–26. doi:10.1093/hmg/ddt538. PMID 24179174.
  15. ↑ Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W, Chan WM, Andrews C, Demer JL, Robertson RL, Mackey DA, Ruddle JB, Bird TD, Gottlob I, Pieh C, Traboulsi EI, Pomeroy SL, Hunter DG, Soul JS, Newlin A, Sabol LJ, Doherty EJ, de Uzcátegui CE, de Uzcátegui N, Collins ML, Sener EC, Wabbels B, Hellebrand H, Meitinger T, de Berardinis T, Magli A, Schiavi C, Pastore-Trossello M, Koc F, Wong AM, Levin AV, Geraghty MT, Descartes M, Flaherty M, Jamieson RV, Møller HU, Meuthen I, Callen DF, Kerwin J, Lindsay S, Meindl A, Gupta ML, Pellman D, Engle EC (8 January 2010). "Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance". Cell. 140 (1): 74–87. doi:10.1016/j.cell.2009.12.011. PMC 3164117. PMID 20074521.
  16. ↑ André N, Braguer D, Brasseur G, Gonçalves A, Lemesle-Meunier D, Guise S, Jordan MA, Briand C (1 October 2000). "Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells'". Cancer Research. 60 (19): 5349–53. PMID 11034069.
  17. ↑ Katsetos CD, Dráber P (2012). "Tubulins as therapeutic targets in cancer: from bench to bedside". Current Pharmaceutical Design. 18 (19): 2778–92. doi:10.2174/138161212800626193. PMID 22390762.
  18. ↑ Ferlini C, Cicchillitti L, Raspaglio G, Bartollino S, Cimitan S, Bertucci C, Mozzetti S, Gallo D, Persico M, Fattorusso C, Campiani G, Scambia G (1 September 2009). "Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77". Cancer Research. 69 (17): 6906–14. doi:10.1158/0008-5472.can-09-0540. PMID 19671798.
  19. ↑ Tuszynski JA, Carpenter EJ, Huzil JT, Malinski W, Luchko T, Luduena RF (2006). "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. doi:10.1387/ijdb.052063jt. PMID 16479502.
  20. ↑ Joe PA, Banerjee A, Ludueña RF (June 2008). "The roles of cys124 and ser239 in the functional properties of human betaIII tubulin". Cell Motility and the Cytoskeleton. 65 (6): 476–86. doi:10.1002/cm.20274. PMID 18435451.
  21. ↑ De Donato M, Mariani M, Petrella L, Martinelli E, Zannoni GF, Vellone V, Ferrandina G, Shahabi S, Scambia G, Ferlini C (March 2012). "Class III β-tubulin and the cytoskeletal gateway for drug resistance in ovarian cancer". Journal of Cellular Physiology. 227 (3): 1034–41. doi:10.1002/jcp.22813. PMID 21520077.
  22. ↑ Gache V, Louwagie M, Garin J, Caudron N, Lafanechere L, Valiron O (4 February 2005). "Identification of proteins binding the native tubulin dimer". Biochemical and Biophysical Research Communications. 327 (1): 35–42. doi:10.1016/j.bbrc.2004.11.138. PMID 15629426.
  23. ↑ Bergsland M, Werme M, Malewicz M, Perlmann T, Muhr J (15 December 2006). "The establishment of neuronal properties is controlled by Sox4 and Sox11". Genes & Development. 20 (24): 3475–86. doi:10.1101/gad.403406. PMC 1698453. PMID 17182872.
  24. ↑ Mozzetti S, Iantomasi R, De Maria I, Prislei S, Mariani M, Camperchioli A, Bartollino S, Gallo D, Scambia G, Ferlini C (15 December 2008). "Molecular mechanisms of patupilone resistance". Cancer Research. 68 (24): 10197–204. doi:10.1158/0008-5472.can-08-2091. PMID 19074887.
  25. ↑ Cochrane DR, Spoelstra NS, Howe EN, Nordeen SK, Richer JK (May 2009). "MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents". Molecular Cancer Therapeutics. 8 (5): 1055–66. doi:10.1158/1535-7163.mct-08-1046. PMC 4573391. PMID 19435871.
  26. ↑ Cochrane DR, Howe EN, Spoelstra NS, Richer JK (2010). "Loss of miR-200c: A Marker of Aggressiveness and Chemoresistance in Female Reproductive Cancers". Journal of Oncology. 2010: 821717. doi:10.1155/2010/821717. PMC 2798671. PMID 20049172.
  27. ↑ 27.0 27.1 Prislei S, Martinelli E, Mariani M, Raspaglio G, Sieber S, Ferrandina G, Shahabi S, Scambia G, Ferlini C (8 February 2013). "MiR-200c and HuR in ovarian cancer". BMC Cancer. 13: 72. doi:10.1186/1471-2407-13-72. PMC 3576328. PMID 23394580.
  28. ↑ Mariani M, Shahabi S, Sieber S, Scambia G, Ferlini C (December 2011). "Class III β-tubulin (TUBB3): more than a biomarker in solid tumors?". Current Molecular Medicine. 11 (9): 726–31. doi:10.2174/156652411798062368. PMID 21999149.
  29. ↑ Karki R, Mariani M, Andreoli M, He S, Scambia G, Shahabi S, Ferlini C (April 2013). "βIII-Tubulin: biomarker of taxane resistance or drug target?". Expert opinion on therapeutic targets. 17 (4): 461–72. doi:10.1517/14728222.2013.766170. PMID 23379899.
  30. ↑ Aoki D, Oda Y, Hattori S, Taguchi K, Ohishi Y, Basaki Y, Oie S, Suzuki N, Kono S, Tsuneyoshi M, Ono M, Yanagawa T, Kuwano M (15 February 2009). "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. doi:10.1158/1078-0432.ccr-08-1274. PMID 19228748.
  31. ↑ Galmarini CM, Treilleux I, Cardoso F, Bernard-Marty C, Durbecq V, Gancberg D, Bissery MC, Paesmans M, Larsimont D, Piccart MJ, Di Leo A, Dumontet C (15 July 2008). "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. doi:10.1158/1078-0432.ccr-07-4741. PMID 18628466.
  32. ↑ Wang Y, Sparano JA, Fineberg S, Stead L, Sunkara J, Horwitz SB, McDaid HM (April 2013). "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. doi:10.1016/j.clbc.2012.11.003. PMC 4039021. PMID 23218766.
  33. ↑ Akasaka K, Maesawa C, Shibazaki M, Maeda F, Takahashi K, Akasaka T, Masuda T (June 2009). "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. doi:10.1038/jid.2008.406. PMID 19122647.
  34. ↑ Gan PP, Pasquier E, Kavallaris M (1 October 2007). "Class III beta-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer". Cancer Research. 67 (19): 9356–63. doi:10.1158/0008-5472.can-07-0509. PMID 17909044.
  35. ↑ McCarroll JA, Gan PP, Liu M, Kavallaris M (15 June 2010). "betaIII-tubulin is a multifunctional protein involved in drug sensitivity and tumorigenesis in non-small cell lung cancer". Cancer Research. 70 (12): 4995–5003. doi:10.1158/0008-5472.can-09-4487. PMID 20501838.
  36. ↑ McCarroll JA, Gan PP, Erlich RB, Liu M, Dwarte T, Sagnella SS, Akerfeldt MC, Yang L, Parker AL, Chang MH, Shum MS, Byrne FL, Kavallaris M (20 November 2014). "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: 415–25. doi:10.1158/0008-5472.CAN-14-2740. PMID 25414139.
  37. ↑ Raspaglio G, Petrillo M, Martinelli E, Li Puma DD, Mariani M, De Donato M, Filippetti F, Mozzetti S, Prislei S, Zannoni GF, Scambia G, Ferlini C (1 June 2014). "Sox9 and Hif-2α regulate TUBB3 gene expression and affect ovarian cancer aggressiveness". Gene. 542 (2): 173–81. 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. PMC 3202616. 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. PMC 3248193. PMID 21576762.
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