Novel target genes of the Ah (dioxin) receptor: Transcriptional induction of N-myristoyltransferase 2

Dioxins are potent mammalian carcinogens and toxins affecting liver, skin, and immune and reproductive systems. The intracellular Ali receptor, a liga nd-dependent transcription factor of the basic region/helix-loop-helix/Per- Ahr/Arnt-Sim homology domain (bHLH-PAS) protein family, mediates responses to dioxins. Target genes of the Ali receptor that mediate dioxin toxicity a nd carcinogenicity are, however, mostly unknown. We used 5L rat hepatoma ce lls to identify dioxin-inducible genes by suppression subtractive hybridiza tion. Eleven cDNA fragments were identified that represented novel sequence s or genes for which induction by dioxins had not been known. N-myristoyltr ansferase 2 (NMT2) is one of the later dioxin-inducible genes. Induction of NMT2 was confirmed in livers of mice in vivo. NMT2 induction was a direct consequence of Ah receptor activation in 5L cells. [H-3]myristic acid incor poration into 5L cell proteins was inducible by dioxins, indicating that pr otein myristoylation is a regulated rather than a housekeeping function and that NMT activity is limiting in noninduced 5L cells. Here we show for the first time that expression of NMT2 and induced protein myristoyltransferas e activity are direct responses to carcinogen exposure. Because inappropria te protein NH2-terminal myristoylation appears to play a role in carcinogen esis, induction of NMT2 may play a central role in dioxin carcinogenicity.