Fernando R. Cabral, Ph.D.

Areas of Interest

Research Interests

Research Information

Cell division, cancer and drug resistance

Microtubules in the cellular cytoskeleton are required for a variety of critical processes including chromosome segregation, cell division, and cell movement. The importance of these cytoplasmic filaments makes them a target for a variety of toxins and medicinally important drugs including the cancer chemotherapeutic agents, vinblastine and taxol

我们的实验室研究和监管功能of microtubules using molecular cellular, and genetic approaches. Our recent work has focused on 3 major questions: 1) How do cells control production of the tubulin subunits used in microtubule assembly? Transfection experiments using epitope-tagged tubulin genes has allowed us to uncover a novel mechanism of translational repression that acts to maintain equal production of the a- and β-tubulin subunits. Future experiments will be aimed at defining the molecular steps in this regulatory pathway. 2)How do cancer cells escape killing by drugs that interfere with microtubule assembly? To address this question, we have isolated and characterized a large number of drug resistant mutants; and, in the process, we have described a new mechanism by which mutations in tubulin counteract drug toxicity. We are currently defining the sites of the mutations and determining whether similar sites are altered in drug-resistant human tumors. 3) How do various tubulin genes determine microtubule behavior and cellular susceptibility to anticancer drugs? Mammalian tubulin is encoded by a multigene family that produces highly homologous but distinct proteins. The roles of these gene products in the cell are being explored by over expressing cDNAs for each of them using a tetracycline regulated promoter, and by depleting the cell of specific tubulins using inhibitory RNA techniques. Ultimately, we hope to get a complete picture of how different tubulin proteins combine to produce specific microtubule characteristics and how tumor cells might vary production of those proteins to gain resistance to chemotherapeutic drugs.

Publications

Publication Information

• Ganguly A, Bhattacharya R,Cabral F. (2012) Control of MCAK degradation and removal from centromeres.Cytoskeleton69, 303–311.
• Ganguly A, Yang H, Sharma R, Patel KD,Cabral F. (2012) The role of microtubules and their dynamics in cell migration.J Biol Chem287, 43359–43369.
• Yin S, Zeng C, Hari M,Cabral F. (2012) Random mutagenesis of β-tubulin defines a set of dispersed mutations that confer paclitaxel resistance.Pharm Res29, 2994–3006.
• Ganguly A,Cabral F. (2011) The arresting action of microtubules in cell motility.Cell Cycle10, 2614–2615.
• Ganguly A, Yang H, Pedroza M, Bhattacharya R,Cabral F. (2011) Mitotic centromere associated kinesin (MCAK) mediates paclitaxel resistance.J Biol Chem286, 36378–36384.
• Yang, H, Ganguly, A, Yin, S, andCabral, F. (2011) Megakaryocyte lineage-specific class VI ®-tubulin suppresses microtubule dynamics, fragments microtubules, and blocks cell division.Cytoskeleton(Hoboken) 68, 175-187.
• Ganguly,A, andCabral, F. (2011) New insights into mechanisms of resistance to microtubule inhibitors.Biochim Biophys Acta1816, 164-171.
• Bhattacharya, R, Yang, H, andCabral, F. (2011) Class V ®-tubulin alters dynamic instability and stimulates microtubule detachment from centrosomes.Mol Biol Cell22, 1025-1034.
• Ganguly,A, Yang, H, andCabral, F. (2011) Class III ®-tubulin counteracts the ability of paclitaxel to inhibit cell migration.Oncotarget2, 368-377.
• Ganguly,A, Yang, H, andCabral, F. (2011) Overexpression of mitotic centromere-associated kinesin stimulates microtubule detachment and confers resistance to Paclitaxel.Mol Cancer Ther10, 929-937.
• Yang, H, Ganguly, A, andCabral, F. (2010) Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs.J Biol Chem. 285, 32242-32250.
• Ganguly,A, Yang, H, andCabral, F. (2010) Paclitaxel dependent cell lines reveal a novel drug activity.Mol Cancer Ther9, 2914-2923.
• Yin, S., Bhattacharya, R., andCabral, F.(2010). Human mutations that confer Paclitaxel resistance.Mol Cancer Ther 9, 327-335.
• Bhattacharya, R, andCabral, F. (2009) Molecular basis for class V ®-tubulin effects on microtubule assembly and paclitaxel resistance.J Biol Chem284, 13023-13032.
• Bhattacharya, R., Frankfurter, A., andCabral, F.(2008). A minor ®-tubulin essential for mammalian cell proliferation.Cell Motil. Cytoskeleton 65, 708-720.
• Ganguly,A., Bhattacharya, R., andCabral, F.(2008). Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement.Cell Cycle 7, 3187-3193.
• Yang, H., andCabral, F.(2007). Heightened sensitivity to paclitaxel in class IVa ®-tubulin transfected cells is lost as expression increases.J. Biol. Chem. 282, 27058-27066.
• Wang, Y., Tian, G., Cowan, N.J., andCabral, F.(2006). Mutations affecting α-tubulin folding and degradation.J. Biol. Chem.281, 13628-13635.
• Wang, Y., Win, S., Blade, K., Cooper, G., Menick, D.R., andCabral, F.(2006) Mutations at Leucine 215 of β-tubulin affect paclitaxel sensitivity by two distinct mechanisms.Biochemistry,45, 185 – 194
• Kamath, K., Wilson. L.,Cabral, F., and Jordan, M.A. (2005) βIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability.J. Biol. Chem.280, 12902-12907.
• Wang, Y., andCabral, F.(2005) Paclitaxel resistance in cells with reduced β-tubulin.Biochem. Biophys.Acta 1744, 245-255.
• Wang, Y., Veeraraghavan, S., andCabral, F.(2004) Intra-allelic suppression of a mutation that stabilizes microtubules and confers resistance to colcemid.Biochemistry43, 8965-8973.
• Battacharya, R., andCabral, F.(2004) A ubiquitous β-tubulin disrupts microtubule assembly and inhibits cell proliferation.Mol. Biol. Cell15, 3123-3131.