Isolation and Analysis of Tubulin Carboxypeptidase: A Chemotherapeutic Target Arising from Tubulin Tyrosine Ligase Suppression in Human Breast Tumors.

摘要

Microtubules are critical to accurate completion of mitosis. In mammalian cells, the microtubule subunit, tubulin, undergoes a cyclic modification by removal and subsequent addition of tyrosine on the alpha-subunit C-terminus. This process uses two specific enzymes, tubulin tyrosine ligase (TTL) and tubulin carboxypeptidase (TCP). We have recently demonstrated that suppression of this cycle may play an important role in tumor development. TTL is frequently and specifically suppressed during tumor growth in situ, suggesting a tumor suppressor function. In the complete absence of TTL activity TCP can cleave the second C-terminal residue of alpha-tubulin, yielding a truncated tubulin designated 'delta 2-tubulin'. Due to TTL suppression, delta 2- tubulin uniquely appears in tumor cells. This specific marker has implications for early breast tumor detection. Further, if suppression of TTL strongly enhances tumor growth, these findings may permit chemotherapeutic intervention through suppression of the TCP to restore the normal tubulin status. We intend to isolate and sequence human TCP as a first step toward determining if suppression of TCP may serve as a unique chemotherapy target.