SUPPRESSION OF TUBULIN TYROSINE LIGASE DURING TUMOR-GROWTH

The C terminus of the tubulin alpha-subunit of most eukaryotic cells u ndergoes a cycle of tyrosination and detyrosination using two specific enzymes, a tubulin tyrosine ligase (TTL) and a tubulin carboxypeptida se, Although this enzyme cycle is conserved in evolution and exhibits rapid turnover, the meaning of this modification has remained elusive, We have isolated several NIH-3T3 derived clonal cell lines that lack TTL (TTL-). TTL- cells contain a unique tubulin isotype (Delta 2-tubul in) that can be detected with specific antibodies, When injected into nude mice, both TTL- cells and TTL- cells stably transfected with TTL cDNA form sarcomas. But in tumors formed from TTL rescued cells, TTL i s systematically lost during tumor growth, A strong selection process has thus acted during tumor growth to suppress TTL activity. In accord with this result, we find suppression of TTL activity in the majority of human tumors assayed with Delta 2-tubulin antibody. We conclude th ere is a widespread loss of TTL activity during tumor growth in situ, suggesting that TTL activity may play a role in tumor cell regulation.