References:
- Wang, Y., Tian, G., Cowan, N.J., and Cabral, 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., and Cabral, F. (2006). Mutations at Leucine 215 of β-tubulin affect paclitaxel sensitivity by two distinct mechanisms. Biochemistray, 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., and Cabral, F (2005). Paclitaxel resistance in cells with reduced β-tubulin. Biochem. Biophys. Acta 1744, 245-255.
- Wang, Y., Veeraraghavan, S., and Cabral, F. (2004). Intra-allelic suppression of a mutation that stabilizes microtubules and confers resistance to colcemid. Biochemistry 43, 8965-8973.
- Battacharya, R., and Cabral, F. (2004). A ubiquitous β-tubulin disrupts microtubule assembly and inhibits cell proliferation. Mol. Biol. Cell 15, 3123-3131.
Fernando Cabral, Ph.D.
Professor
UTHSC-Medical School, (713) 500 - 7485
Fernando.R.Cabral@uth.tmc.edu
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
Our laboratory studies the function and regulation 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.
