I Study of Nucleation stage of microtubule assembly

Nisha Elizabeth Thomas, Shashikala S and Suparna Sengupta
Microtubules are a major cytoskeletal component with many important functions. They are involved in cell division, maintenance of cell shape and polarity and transport of nutrients and organelles. Nucleation stage or the formation of oligomers is a crucial intermediate stage of microtubule assembly from its component proten tubulin. In a cell, improper nucleation may give rise to lack of polarity of interphase and mitotic cell, distorted shape and loss of directionality of microtubule mediated transport. Many proteins and antimitotic agents influence the nucleation stage of microtubule assembly.

• Gamma-tubulin associated proteins and their role in microtubule function
  Gamma tubulin is a major protein involved in the in vivo nucleation of microtubules. In the cells, gamma tubulin exists as a complex termed as the gamma tubulin ring complex in association with other proteins. It usually nucleates microtubules from the centrosomes, although it is present in the cytoplasm, the function of which is not known. The role of gamma tubulin complex and its accessory proteins are being studied in normal cells as well as in abnormal situations like cancer.
• Effect of some anticancer drugs on the nucleation stage
  Microtubule inducing antimitotic compounds stabilize microtubules from cold, colchicine and calcium induced depolymerization. The existing belief is that they basically bind to tubulin in the polymeric stage only with high affinity and thus exert their effect. However, these drugs induce hypernucleation in vitro and in vivo. We are studying the effect of microtubule inducing anticancer agents on the nucleation stage of assembly.

II Microtubule targeting compounds as potential anticancer agents

Sannu Ann Thomas, Smreti Vasudevan, Reshma Thankachy, Swathi U.Lekshmi, Praveen Kumar Dubba and Suparna Sengupta

Microtubules are one of the major cytoskeletal components which perform many functions. Due to their essential role in the spindle formation and chromosome separation, they are a popular target for anticancer drug development and some of them are widely used in the clinic. Microtubule binding compounds affect microtubule dynamics and the polymer stability, thereby giving rise to abnormal spindle leading the cells to a block in the G2/M phase, which normally get destined to apoptosis. Some of them affect the G2/M or spindle check point also thereby affecting their antimitotic property. Improper binding to tubulin and defective checkpoint control may give rise to resistance to anticancer drugs. By affecting microtubule dynamics, microtubule binding drugs may also act as antiangiogenic compounds as they alter the motility of endothelial cells and disrupt tumour vasculature. We are studying the mechanism of action of microtubule targeting novel cytotoxic compounds in cancer cells. We are also exploring their antiangiogenic potential and the mechanism involved. The pathway leading to apoptosis after a mitotic block or aberrant mitotic exit is also being studied. Effort is on to develop a few promising compounds as anticancer drugs through cellular and animal models. The resistance mechanism of antimitotic compounds in cancer cells are also under study. We mostly use biochemical, biophysical and cell biology techniques for our study.

Extramural Fundings Received:

Ongoing Research Projects as PI

Completed Research Projects as PI: