Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)-
alanine] has the unique property of converting ras- or c-erbB-2 transformed phenotype to normal. The administration of
azatyrosine also inhibits
tumor formation in transgenic mice harboring the normal human c-Ha-ras which is mutated during treatment with various chemical
carcinogens. To elucidate the molecular mechanism, we investigated how
azatyrosine functions and what are its major targets.
Azatyrosine functions downstream of ras;
azatyrosine does not alter either the level of
GTP-bound Ras or the total amount of Ras. Instead,
azatyrosine inhibits the activation of c-Raf-1
kinase by oncogenic c-ErbB-2, resulting in inactivation of AP1. It is interesting that
azatyrosine also restores the expression of the rhoB gene, the product of which regulates the formation of actin stress fibers.
Azatyrosine is incorporated into cellular
proteins to replace
tyrosine. Several experiments indicate that replacement of
tyrosine is likely to be a cause for its conversion of transformed phenotype to normal. To prove this hypothesis, we are attempting to develop a mutant of
tyrosyl-tRNA synthetase that, unlike wild type, can aminoacylate
azatyrosine more efficiently than can
tyrosine.