Tubulin beta-3 chain explained

Tubulin beta-3 chain, Class III β-tubulin, 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] In humans, it is encoded by the TUBB3 gene.[4] [5] [6] [7] [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 tubulin beta-3 chain.

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 and References

  1. Sullivan KF, Cleveland DW . 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 . 3459176 . 10.1073/pnas.83.12.4327 . 323725. 1986PNAS...83.4327S . free .
  2. Caccamo DV, Herman MM, Frankfurter A, Katsetos CD, Collins VP, Rubinstein LJ . 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 . 2817080 . 1880094.
  3. De Gendt K, Denolet E, Willems A, Daniels VW, Clinckemalie L, Denayer S, Wilkinson MF, Claessens F, Swinnen JV, Verhoeven G . 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 . 21734264 . 10.1095/biolreprod.110.090704 . 4480425.
  4. Ranganathan S, Dexter DW, Benetatos CA, Hudes GR . 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 . 9473684 . 10.1016/s0167-4781(97)00168-1 .
  5. Venter JC . Identification of new human receptor and transporter genes by high throughput cDNA (EST) sequencing . J Pharm Pharmacol . Suppl 1 . 355–60 . Jun 1993 . 8098743 . 45 .
  6. Web site: Entrez Gene: TUBB3 tubulin, beta 3.
  7. Ferlini C, Raspaglio G, Cicchillitti L, Mozzetti S, Prislei S, Bartollino S, Scambia G . Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work? . . 7 . 8 . 704–12 . December 2007 . 18220531 . 10.2174/156800907783220453.
  8. Cicchillitti L, Penci R, Di Michele M, Filippetti F, Rotilio D, Donati MB, Scambia G, Ferlini C . Proteomic characterization of cytoskeletal and mitochondrial class III beta-tubulin. . Molecular Cancer Therapeutics . 7 . 7 . 2070–9 . July 2008 . 18645017 . 10.1158/1535-7163.mct-07-2370. 26212762 . free .
  9. 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 . 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 . 20829227 . 10.1093/hmg/ddq377 . 3298850.
  10. Raspaglio G, Filippetti F, Prislei S, Penci R, De Maria I, Cicchillitti L, Mozzetti S, Scambia G, Ferlini C . 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 . 18178340 . 10.1016/j.gene.2007.11.015.
  11. Raspaglio G, De Maria I, Filippetti F, Martinelli E, Zannoni GF, Prislei S, Ferrandina G, Shahabi S, Scambia G, Ferlini C . HuR regulates beta-tubulin isotype expression in ovarian cancer. . Cancer Research . 70 . 14 . 5891–900 . 15 July 2010 . 20587520 . 10.1158/0008-5472.can-09-4656. free .
  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 . Aberrant localization of the neuronal class III beta-tubulin in astrocytomas. . Archives of Pathology & Laboratory Medicine . 125 . 5 . 613–24 . May 2001 . 11300931 . 10.5858/2001-125-0613-ALOTNC.
  13. Sieber-Blum M, Schnell L, Grim M, Hu YF, Schneider R, Schwab ME . 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 . 16626970 . 10.1016/j.mcn.2006.02.003. 10388161 .
  14. Saillour Y, Broix L, Bruel-Jungerman E, Lebrun N, Muraca G, Rucci J, Poirier K, Belvindrah R, Francis F, Chelly J . 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 . 24179174 . 10.1093/hmg/ddt538.
  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 . Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. . Cell . 140 . 1 . 74–87 . 8 January 2010 . 20074521 . 10.1016/j.cell.2009.12.011 . 3164117.
  16. André N, Braguer D, Brasseur G, Gonçalves A, Lemesle-Meunier D, Guise S, Jordan MA, Briand C . Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells'. . Cancer Research . 60 . 19 . 5349–53 . 1 October 2000 . 11034069 .
  17. Katsetos CD, Dráber P . Tubulins as therapeutic targets in cancer: from bench to bedside. . Current Pharmaceutical Design . 18 . 19 . 2778–92 . 2012 . 22390762 . 10.2174/138161212800626193.
  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 . Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. . Cancer Research . 69 . 17 . 6906–14 . 1 September 2009 . 19671798 . 10.1158/0008-5472.can-09-0540. free .
  19. Tuszynski JA, Carpenter EJ, Huzil JT, Malinski W, Luchko T, Luduena RF . 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 . 16479502 . 10.1387/ijdb.052063jt. free .
  20. Joe PA, Banerjee A, Ludueña RF . 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 . 18435451 . 10.1002/cm.20274.
  21. De Donato M, Mariani M, Petrella L, Martinelli E, Zannoni GF, Vellone V, Ferrandina G, Shahabi S, Scambia G, Ferlini C . Class III β-tubulin and the cytoskeletal gateway for drug resistance in ovarian cancer. . Journal of Cellular Physiology . 227 . 3 . 1034–41 . March 2012 . 21520077 . 10.1002/jcp.22813. 24222768 . free .
  22. Gache V, Louwagie M, Garin J, Caudron N, Lafanechere L, Valiron O . Identification of proteins binding the native tubulin dimer. . Biochemical and Biophysical Research Communications . 327 . 1 . 35–42 . 4 February 2005 . 15629426 . 10.1016/j.bbrc.2004.11.138. 10.1.1.321.8904 . 16958013 .
  23. Bergsland M, Werme M, Malewicz M, Perlmann T, Muhr J . The establishment of neuronal properties is controlled by Sox4 and Sox11. . Genes & Development . 20 . 24 . 3475–86 . 15 December 2006 . 17182872 . 10.1101/gad.403406 . 1698453.
  24. Mozzetti S, Iantomasi R, De Maria I, Prislei S, Mariani M, Camperchioli A, Bartollino S, Gallo D, Scambia G, Ferlini C . Molecular mechanisms of patupilone resistance. . Cancer Research . 68 . 24 . 10197–204 . 15 December 2008 . 19074887 . 10.1158/0008-5472.can-08-2091. free .
  25. Cochrane DR, Spoelstra NS, Howe EN, Nordeen SK, Richer JK . MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents. . Molecular Cancer Therapeutics . 8 . 5 . 1055–66 . May 2009 . 19435871 . 10.1158/1535-7163.mct-08-1046 . 4573391.
  26. Cochrane DR, Howe EN, Spoelstra NS, Richer JK . Loss of miR-200c: A Marker of Aggressiveness and Chemoresistance in Female Reproductive Cancers. . Journal of Oncology . 2010 . 821717 . 2010 . 20049172 . 10.1155/2010/821717 . 2798671. free .
  27. Prislei S, Martinelli E, Mariani M, Raspaglio G, Sieber S, Ferrandina G, Shahabi S, Scambia G, Ferlini C . MiR-200c and HuR in ovarian cancer. . BMC Cancer . 13 . 72 . 8 February 2013 . 23394580 . 10.1186/1471-2407-13-72 . 3576328 . free .
  28. Mariani M, Shahabi S, Sieber S, Scambia G, Ferlini C . Class III β-tubulin (TUBB3): more than a biomarker in solid tumors? . Current Molecular Medicine . 11 . 9 . 726–31 . December 2011 . 21999149 . 10.2174/156652411798062368.
  29. Karki R, Mariani M, Andreoli M, He S, Scambia G, Shahabi S, Ferlini C . βIII-Tubulin: biomarker of taxane resistance or drug target? . Expert Opinion on Therapeutic Targets . 17 . 4 . 461–72 . April 2013 . 23379899 . 10.1517/14728222.2013.766170. 26229777 .
  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 . 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 . 19228748 . 10.1158/1078-0432.ccr-08-1274. 25857848 . free .
  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 . 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 . 18628466 . 10.1158/1078-0432.ccr-07-4741. 7703873 . free .
  32. Wang Y, Sparano JA, Fineberg S, Stead L, Sunkara J, Horwitz SB, McDaid HM . 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 . 23218766 . 10.1016/j.clbc.2012.11.003 . 4039021.
  33. Akasaka K, Maesawa C, Shibazaki M, Maeda F, Takahashi K, Akasaka T, Masuda T . 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 . 19122647 . 10.1038/jid.2008.406. free .
  34. Maria Kavallaris . Gan PP, Pasquier E, Kavallaris M . Class III beta-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer. . Cancer Research . 67 . 19 . 9356–63 . 1 October 2007 . 17909044 . 10.1158/0008-5472.can-07-0509. free .
  35. McCarroll JA, Gan PP, Liu M, Kavallaris M . 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 . 20501838 . 10.1158/0008-5472.can-09-4487. free .
  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 . TUBB3/βIII-Tubulin Acts through the PTEN/AKT Signaling Axis to Promote Tumorigenesis and Anoikis Resistance in Non-Small Cell Lung Cancer. . Cancer Research . 20 November 2014 . 25414139 . 10.1158/0008-5472.CAN-14-2740 . 75 . 2 . 415–25. free . 1959.4/unsworks_39441 . free .
  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 . Sox9 and Hif-2α regulate TUBB3 gene expression and affect ovarian cancer aggressiveness. . Gene . 542 . 2 . 173–81 . 1 June 2014 . 24661907 . 10.1016/j.gene.2014.03.037.
  38. Karki . R . Marini . M . Andreoli. M. He. S. Scambia. G. Shahabi. S. Ferlini. C . βIII-Tubulin: biomarker of taxane resistance or drug target?. Expert Opin Ther Targets . 17 . 4 . 461–72 . 2013 . 10.1517/14728222.2013.766170 . 23379899. 26229777 .
  39. Ferrandina . G . Zannoni . GF . Martinelli . E. Paglia. A. Gallotta. V. Mozzetti . S. Scambia . G . Ferlini. C. Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients.. Clin. Cancer Res. . 12 . 9 . 2774–9. 2006 . 16675570 . 10.1158/1078-0432.CCR-05-2715. 85980035 . free .
  40. Ganguly . A . Cabral . F . New insights into mechanisms of resistance to microtubule inhibitors. Biochim Biophys Acta . 1816 . 2 . 2774–9. 2011 . 21741453 . 10.1016/j.bbcan.2011.06.001 . 3202616.
  41. Ganguly . A . Yang . H . Cabral . F . Class III β-tubulin counteracts the ability of paclitaxel to inhibit cell migration.. Oncotarget . 2 . 5 . 368–377. 2011 . 21576762 . 3248193. 10.18632/oncotarget.250.

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