Mammalian Spermatozoa
Claude Gagnon in Controls of Sperm Motility, 2020
Various studies have shown that multiple forms of α- and β-tubulins exist in the same organism and even the same tissue,14-17 the testis being no exception.18-20 Unique β- and α-tubulin genes have been shown to be expressed in the testis.21-25 In Drosophila, testis-specific β2-tublin mutations do not alter the early mitotic divisions but abrogate subsequent mi-crotubule-mediated events, including meiosis, and assembly of the axoneme.21-23 Pratt et al.25 have identified a novel cα2-tubulin in chicken testes containing a nonconservative carboxy terminus sequence which lacks a terminal tyrosine and thus probably does not participate in the usual cycle of tyrosination/detyrosination.26 Because there is a preferential association of detyrosinated tubulin subunits with stable microtubules of centrioles and primary cilia in cultured fibroblasts and of axonemes and basal bodies in sperm and tracheal cells,27 Pratt et al.25 suggest that the ca2-tubulin may be involved in the assembly of stable microtubules in the chicken spermatid manchette and axoneme. The most compelling evidence for a specific testicular α-tubulin in mammals, which may take part in the construction of the manchette or axoneme (events which occur solely in spermiogenesis), is the isolation of a cDNA clone from mouse testis which is exclusively expressed in postmeiotic testicular cells.24,28-29
Cell division
Frank J. Dye in Human Life Before Birth, 2019
Like the chromosomes, the spindle plays an important role in mitosis. Unlike the chromosomes, the spindle is a short-lived cellular structure that comes and goes according to the cell's needs. Two microtubule-organizing centers (MTOCs; classically called centrosomes) make the spindle during the earliest stage of mitosis (prophase). The spindle is composed of a protein called tubulin that has been organized into microtubules. As the chromosomes condense during prophase, the centrosome divides, and the two resulting daughter centrosomes move to opposite ends of the nucleus, organizing the spindle as they go (see Figure 3.6). When the nuclear membrane disappears at the end of prophase, initiating prometaphase, the condensed chromosomes are captured by spindle fibers (bundles of microtubules).
Specific Therapy for Leukemias
Tariq I Mughal, John M Goldman, Sabena T Mughal in Understanding Leukemias, Lymphomas, and Myelomas, 2017
Dexamethasone is a related drug which might confer a greater effect on cancer cells than prednisolone. It also has the advantage of penetrating the CNS more effectively. Vincristine is a potent cytotoxic drug extracted from the periwinkle plant Catharanthus (vinca) rosea. It works directly on cancer cells by binding to the protein tubulin and preventing cell division. Tubulin forms fibers that help cell division to progress in an orderly fashion. Since all leukemia cells do not divide at the same time, vincristine is given weekly in the hope that eventually all the cells will be affected. Vincristine can cause constipation and stomach cramps and rarely paresthesias (neuropathy). Given in excess, it can lead to temporary paralysis of the bowel or of certain nerves, resulting in muscle weakness which may result in foot-drop, wrist-drop, and facial paralysis. Most of these effects are completely reversible and are rarely seen in current treatment schedules.
Design, synthesis and evaluation of dihydro-1H-indene derivatives as novel tubulin polymerisation inhibitors with anti-angiogenic and antitumor potency
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Shengtao Xu, Yijun Sun, Peng Wang, Yuchen Tan, Lei Shi, Jian Chen
Tubulin plays an important role in a variety of cellular processes including cell proliferation, cell signalling and cell morphology, which is one of the attractive targets for new antitumor drugs discovery1–3. Microtubule-targeting agents (MTAs) could inhibit the polymerisation or destabilisation of microtubules by altering its dynamics in cells4. Up to date, six major binding sites have been identified on tubulin, including colchicine binding site (CBS), pironetin binding site, laulimalide binding site, vinca binding site, maytansine binding site, and taxane binding site5,6. Taxanes and vinblastine were examples as MTAs approved by FDA and used for the treatment of solid tumours7,8. However, the application of these drugs in clinic was limited due to their multidrug resistance (MDR)9–11.
Mirvetuximab soravtansine for platinum-resistant epithelial ovarian cancer
Published in Expert Review of Anticancer Therapy, 2023
Rebecca L. Porter, Ursula A. Matulonis
One important consideration as mirvetuximab becomes part of the standard treatment of EOC is the likely development of treatment resistance. Drug resistance is known to occur with ADCs at several different points in their mechanism of acting, including: i) premature release of payload, ii) downregulation of antigen target, iii) reduced lysosomal proteolytic activity, iv) development of mutations in genes encoding tubulin composition, v) increased drug clearance from the cell and the vi) generation of antidrug antibodies that can target the various components of ADCs (reviewed in [30]. The continued incorporation of translational research within trials of mirvetuximab will be imperative to understanding the specific mechanisms of primary and acquired resistance to this ADC. In addition, while the concordance rate of FRα expression between archival tissue and fresh biopsies has been tested [56], whether FRα expression varies between primary and metastatic sites and if this influences the efficacy of mirvetuximab in HGSOC remains unknown. Moreover, distribution of FRα expression within tumors and across multiple metastatic sites, and the possible correlation with response to therapy, remains to be explored and may serve as a future predictive biomarker. In addition, the possible penetration of mirvetuximab into the central nervous system is also not known and will need to be studied. There is now increasing evidence to support CNS penetration of other ADCs and CNS responses in patients with brain metastases [26,90,91].
Discovery of dual tubulin-NEDDylation inhibitors with antiproliferative activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Microtubules as dynamic protein polymers of α- and β-tubulin play essential roles in a range of cellular processes, such as intracellular transport, cell division, cell growth, cell shape maintenance, and cell motility1. Recently, microtubule-targeting agents interacted with tubulin have been widely developed for cancer therapy2. N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivative 1 (Figure 1) inhibited tubulin polymerisation and exhibited the potent antiproliferative activity3. Tubulin polymerisation inhibitor 2 could induce intracellular reactive oxygen species (ROS) production and mitochondrial depolarization4. Compound 3 induced the G2/M phase arrest and cell apoptosis against MGC803 cells by targeting tubulin5. Tubulin polymerisation inhibitor 4 could interrupt the formation of microtubule network by inhibiting the tubulin polymerisation with an IC50 value of 4.96 μM6. Thus, tubulin has become an important target for the development of anticancer agents7.
Related Knowledge Centers
- Cytoskeleton
- DNA
- Eukaryote
- Globular Protein
- Microtubule
- Molecular Biology
- Cancer
- Mitosis
- Protein Superfamily
- Discovery & Development of Tubulin Inhibitors
- DNA