Disease relevance of Azatyrosine

• Application of L-beta-(5-hydroxy-2-pyridyl)alanine (azatyrosine) to the skin at a dose of 2 mg/mouse once every 3 days after initiation with 7,12-dimethylbenz[a]anthracene greatly reduced the percentage incidence, number per mouse, and size of papillomas [1].
• A mutant Escherichia coli tyrosyl-tRNA synthetase utilizes the unnatural amino acid azatyrosine more efficiently than tyrosine [2].
• Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)-alanine], an antibiotic isolated from Streptomyces chibanensis, inhibited the growth of NIH 3T3 cells transformed by the activated human c-Ha-ras gene but did not significantly inhibit the growth of normal NIH 3T3 cells [3].
• Sensitivity to the parvovirus minute virus of mice as a probe for azatyrosine-mediated phenotypic reversion of spontaneously transformed cells [4].
• Human pancreatic adenocarcinoma cells, which are known to contain an amplified activated c-Ki-ras gene and an amplified c-myc gene, were also converted to flat and giant revertant cells by treatment with azatyrosine [3].

High impact information on Azatyrosine

• Isolation of genes specifically expressed in flat revertant cells derived from activated ras-transformed NIH 3T3 cells by treatment with azatyrosine [5].
• The revertant cells maintain their normal phenotype during prolonged culture in the absence of azatyrosine, although activated p21ras is still expressed [5].
• The antibiotic azatyrosine [DL-3-(5-hydroxy-2-pyridyl)alanine] suppressed meiotic maturation in oocytes induced by progesterone or the combination of [Val12]p21Ha-ras microinjection and insulin-like growth factor I. The suppression was dose-dependent in the range of 20-250 microM azatyrosine [6].
• Azatyrosine has been shown by others [Shindo-Okada, N., Makabe, O., Nagahara, H. & Nishimura, S. (1989) Mol. Carcinog. 2, 159-167] to inhibit the growth of ras-transformed cells without affecting that of nontransformed cells [6].
• We previously reported that mouse NIH 3T3 cells transformed by transfection of activated human c-Ha-ras become apparently normal upon treatment with the antibiotic azatyrosine [5].

Chemical compound and disease context of Azatyrosine

• Administration of azatyrosine i.p. at a dose of 2 mg/mouse once every 2 days for 12 weeks after initiation with methylnitrosourea completely prevented the formation of forestomach papillomas [1].

Biological context of Azatyrosine

• The normal phenotype induced by azatyrosine could be due to activation of expression of some cellular gene(s) in the cells that results in suppression of ras function [5].
• The antibiotic azatyrosine suppresses progesterone or [Val12]p21 Ha-ras/insulin-like growth factor I-induced germinal vesicle breakdown and tyrosine phosphorylation of Xenopus mitogen-activated protein kinase in oocytes [6].
• These results suggest that utilization of F130S TyrRS for in vivo protein biosynthesis may lead to efficient production of azatyrosine-containing alloproteins [2].
• The desired TyrRS mutants were selected by screening for in vivo azatyrosine incorporation of E. coli cells transformed with the mutant tyrS plasmids [2].
• Thus, the revertant phenotype induced by azatyrosine does not result from inactivation of v-H-ras oncogene or inhibition of its expression [7].

Anatomical context of Azatyrosine

• Lack of an effect of azatyrosine on germinal vesicle breakdown induced by the microinjection of an extract from mature oocytes, however, suggests that azatryosine is acting upstream of maturation-promoting factor activation [6].
• After 7 days of azatyrosine treatment, approximately 30% of MTSV1-7 (ras) cells survived, and revertant cell lines were selected by random cloning [7].
• It was shown that azatyrosine also inhibited differentiation-associated growth arrest of PC12 cells induced by oncogenic Ras [8].
• Azatyrosine inhibits neurite outgrowth of PC12 cells induced by oncogenic Ras [8].
• Isolation of azatyrosine-induced revertants from ras-transformed human mammary epithelial cells [7].

Associations of Azatyrosine with other chemical compounds

• Kinetic analysis of aminoacyl-tRNA formation by the wild-type and mutated F130S TyrRS enzymes showed that the specificity for azatyrosine, measured by the ratios of k(cat)/K(m) for tyrosine and the analogue, increased from 17 to 36 as a result of the F130S mutation [2].
• An antibiotic, azatyrosine [L-beta-(5-hydroxy-2-pyridyl) alanine], specifically converts ras-, raf- or c-erbB2 (neu)-transformed NIH3T3 cells to apparently normal phenotype [8].
• The reversion induced by azatyrosine is permanent, and the phenotype of the revertant cells does not change even after prolonged culture in the absence of azatyrosine [N. Shindo-Okada, O. Manabe, H. Nagahara & S. Nishimura (1989). Mol. Carcinogen., 2, 159-167] [8].
• Neither azatyrosine isomer was shown to be a substrate for beta-elimination, based on coupled assays with lactate dehydrogenase and on HPLC measurements [9].
• Analysis of the biologic properties of these azatyrosine-resistant cell lines revealed: (1) a significant reduction in in vitro growth rates; (2) a decreased rate of DNA synthesis as measured by thymidine uptake; and (3) a decreased ability for colony formation in soft agar [10].

Gene context of Azatyrosine

• Incubation of disrupted cells with an antibody that neutralized the function of c-ras (Y13-259) abolished receptor-mediated stimulation of MAPK as did acute addition of 200 microM azatyrosine [11].
• Permanent conversion of mouse and human cells transformed by activated ras or raf genes to apparently normal cells by treatment with the antibiotic azatyrosine [3].
• Treatment with azatyrosine caused similar conversion of NIH 3T3 cells transformed by activated c-Ki-ras, N-ras, or c-raf to apparently normal cells, but NIH 3T3 cells transformed by hst or ret were not exclusively converted by azatyrosine [3].
• Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)-alanine] has the unique property of converting ras- or c-erbB-2 transformed phenotype to normal [12].
• Azatyrosine did not induce GFAP in ras/myc SFME cells, but inhibited growth [13].

Analytical, diagnostic and therapeutic context of Azatyrosine

• Non-transformed revertant clones were isolated from the ras-transformed MTSV1-7 (ras) cell line, after treatment with the antibiotic azatyrosine [7].

References