Article

The β isotypes of tubulin in neuronal differentiation

Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
Cytoskeleton (Impact Factor: 3.01). 07/2010; 67(7):431-41. DOI: 10.1002/cm.20455
Source: PubMed

ABSTRACT The differences among the vertebrate beta isotypes of tubulin are highly conserved in evolution, suggesting that they have functional significance. To address this, we have used differentiating neuroblastoma cells as a model system. These cells express the betaI, betaII, and betaIII isotypes. Although there is no difference prior to differentiation, a striking difference is seen after differentiation. Both betaI and betaIII occur in cell bodies and neurites, while betaII occurs mostly in neurites. Knocking down betaI causes a large decrease in cell viability while silencing betaII and betaIII does not. Knocking down betaII causes a large decrease in neurite outgrowth without affecting viability. Knocking down betaIII has little effect on neurite outgrowth and only decreases viability if cells are treated with glutamate and glycine, a combination known to generate free radicals and reactive oxygen species. It appears, therefore, that betaI is required for cell viability, betaII for neurite outgrowth and betaIII for protection against free radicals and reactive oxygen species.

0 Followers
 · 
92 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Major advances in the genomics and epigenomics of diffuse gliomas and glioblastoma to date have not been translated into effective therapy, necessitating pursuit of alternative treatment approaches for these therapeutically challenging tumors. Current knowledge of microtubules in cancer and the development of new microtubule-based treatment strategies for high-grade gliomas are the topic in this review article. Discussed are cellular, molecular, and pharmacologic aspects of the microtubule cytoskeleton underlying mitosis and interactions with other cellular partners involved in cell cycle progression, directional cell migration, and tumor invasion. Special focus is placed on (1) the aberrant overexpression of βIII-tubulin, a survival factor associated with hypoxic tumor microenvironment and dynamic instability of microtubules; (2) the ectopic overexpression of γ-tubulin, which in addition to its conventional role as a microtubule-nucleating protein has recently emerged as a transcription factor interacting with oncogenes and kinases; (3) the microtubule-severing ATPase spastin and its emerging role in cell motility of glioblastoma cells; and (4) the modulating role of posttranslational modifications of tubulin in the context of interaction of microtubules with motor proteins. Specific antineoplastic strategies discussed include downregulation of targeted molecules aimed at achieving a sensitization effect on currently used mainstay therapies. The potential role of new classes of tubulin-binding agents and ATPase inhibitors is also examined. Understanding the cellular and molecular mechanisms underpinning the distinct behaviors of microtubules in glioma tumorigenesis and drug resistance is key to the discovery of novel molecular targets that will fundamentally change the prognostic outlook of patients with diffuse high-grade gliomas. Copyright © 2015 Elsevier Inc. All rights reserved.
    Seminars in pediatric neurology 04/2015; 22(1). DOI:10.1016/j.spen.2015.03.009 · 1.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gliomas represent approximately 70% of all pediatric brain tumors, and most of these are of astrocytic lineage; furthermore, malignant or high-grade astrocytomas account for approximately 20% of pediatric astrocytoma. Treatment options for pediatric patients with glioma are limited. Although low-grade astrocytomas are relatively slow-growing tumors that can often be cured through surgical resection, a significant proportion of cases recur, as such, new treatments are desperately needed. This review covers the various approaches that are currently being made toward improving the prognosis of pediatric patients with glioma by pursuing pediatric-selective mutant drug targets with emerging small molecules. Copyright © 2015 Elsevier Inc. All rights reserved.
    Seminars in Pediatric Neurology 12/2014; 22(1). DOI:10.1016/j.spen.2014.12.003 · 1.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: NAP (NAPVSIPQ, davunetide) is a microtubule stabilizing peptide drug candidate. Here, we set out to identify NAP-like peptides that provide neuroprotection and reduce tau pathology. NAP-like peptides were derived using publically available search engines, which identified sequence homologies in the microtubule subunit tubulin and in the microtubule associated protein, tau. NATLSIHQ (NAT) and STPTAIPQ were derived from tubulin, and TAPVPMPD (TAP) was derived from tau. All peptides provided neuroprotection against the Alzheimer's disease (AD) toxin, the amyloid-β 1-42 peptide, although NAT and TAP were much more potent than STPTAIPQ. NAT also protected astrocytes, while STPTAIPQ was active only at micromolar concentrations. Because NAT and TAP were much more potent than STPTAIPQ in neuroprotection, those peptides were also tested for inhibition of tau-like aggregation (the second protein hallmark pathology of AD). Both NAT and TAP inhibited tau-like aggregation, with NAT being active over a very broad concentration range. NAT also protected in vivo in a frontotemporal dementia transgenic mouse model (Tau-Tg), when tested at the age of ~10 months. Results showed significantly decreased levels of the NAP parent protein, activity-dependent neuroprotective protein in the cerebral cortex of the Tau-Tg which was increased back to normal levels by NAT treatment. This was coupled to protection of Brain-Body weight ratio in the compromised Tau-Tg. With AD being the major tauopathy and with tau taking part in frontotemporal dementia, novel NAP derivatives that reduce tauopathy and provide neuroprotection are of basic and clinical interest.
    Journal of Alzheimer's disease: JAD 02/2014; 40. DOI:10.3233/JAD-131664 · 3.61 Impact Factor