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Azatyrosine: Mechanism of Action for Conversion of Transformed Phenotype to Normal
Author(s) -
MONDEN YOSHIAKI,
HAMANOTAKAKU FUMIE,
SHINDOOKADA NOBUKO,
NISHIMURA SUSUMU
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb09406.x
Subject(s) - mutant , phenotype , tyrosine , rhob , chemistry , microbiology and biotechnology , tyrosine kinase , biology , biochemistry , mechanism of action , wild type , gene , signal transduction , in vitro , rhoa
A bstract : Azatyrosine [L‐β‐(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 rho B 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 ransformed 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.