4-Phenylbutyrate (PB) induces differentiation and is being intensively studied as a treatment for brain, prostate, breast, and hematopoietic
cancer. While many different primary targets for PB have been proposed, the mechanism by which it causes cellular differentiation remains unknown. To identify the primary cellular target, we investigated its effects on Saccharomyces cerevisiae and showed that it inhibits
tryptophan transport. We show here that PB and
sorbic acid induce an
ubiquitin-dependent turnover of the
tryptophan permease Tat2p. However, the inhibition of transport is not a consequence of the loss of Tat2p, since it also occurs when turnover is prevented by deleting the Tat2p ubiquitination sites. When we tested the effects of PB and other growth inhibitory agents on the growth of
amino acid auxotrophs, we found that several auxotrophs are hypersensitive to a number of chemically unrelated agents, including PB and some, but not all, weak
acids; and this sensitivity is due to the inhibition of
amino acid transport. For the inhibitory weak
acids, inhibition is not confined to
aromatic amino acid auxotrophs, nor is it a general weak
acid stress response, since the degree of inhibition is independent of weak
acid hydrophobicity and p Ka. Our results show that diverse agents affect the activity of the Tat2p
permease rather than its stability and suggest the hypothesis that the anti-neoplastic action of PB is due to a decrease in the activity of surface receptors or other
membrane proteins needed to maintain the transformed state.