Cofactors that Mediate Facilitated Tubulin Folding as Novel Targets for Breast Cancer Chemotherapy
NEW YORK UNIV MEDICAL CENTER NY
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Microtubules are dynamic polymers that are essential to cell division as a major component of the mitotic spindle, and consist largely of two soluble proteins termed a- and 3-tubulin. The biological activity of these proteins depends critically on their proper folding. This is a multi-step process involving ATP-dependent interaction with cytosolic chaperonin, followed by an obligatory cascade of ATP-independent interactions with several protein cofactors. These proteins termed cofactors A, B, C, D and E function specifically in the a- and 3-tubulin folding pathways. The goal of the project proposed in this application is to use the tools of contemporary molecular biology to search for compounds that might act as specific inhibitors of one or more of these proteins. Because the synthesis of tubulin is essential for cell division, reagents that specifically prevent the productive folding of tubulin are likely to be useful as novel chemotherapeutic agents for the treatment of breast cancer, either alone or in combination with existing drugs. Because their mode of action would target de novo production of functional tubulin rather than the biochemical properties of tubulin per se, the development of such drugs would result in a new class of anti-tumor compounds.
- Medicine and Medical Research