4S polycyclic aromatic hydrocarbon receptor (glycine N-methyltransferase) and the aryl hydrocarbon receptor nuclear translocator (hypoxia inducible factor-1β) interaction in Chinese hamster ovary and rat hepatoma cells: 4S PAH-R/ARNT hetero-oligomers?

Abstract

Rat CYP1A1 promoter-luciferase, transiently transfected wild-type and 4S PAH receptor (glycine N-methyl transferase, GNMT)-transformed Chinese hamster ovary (CHO) cells were exposed to benzo[a]pyrene and assayed for luciferase activity as an indicator of CYP1A1 promoter activity. CHO cells transformed with the rat 4S PAH receptor/GNMT expression vector had twice the induction level of luciferase activity with respect to wild-type CHO cells in concert with previously published reports that the 4S PAH receptor/GNMT mediates benzo[a]pyrene induction of CYP1A1 gene expression. Lysates of GNMT-transformed CHO cells and wild-type H4IIE rat hepatoma cells exposed to benzo[a]pyrene were immuno-precipitated with anti-GNMT antibodies, separated by SDS-polyacrylamide gel electrophoresis and transferred to PVDF membrane for Western blot analysis with anti-aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1β) antibodies. Results of this analysis indicated that the 4S PAH receptor/GNMT forms a hetero-oligomer (dimer?) with ARNT/HIF-1β which dissociates in the presence of B[a]P. These observations further indicate the role of GNMT (which has been shown to be multifunctional) and B[a]P in the induction of CYP1A1 and also a potential role of GNMT in the modulation of hypoxia inducible factor-1 function with respect to the HIF-1β subunit (ARNT).

Nuclear localization dictates hepatocarcinogenesis suppression by glycine N-methyltransferase

“…Different mechanisms support the suppressive action of GNMT. GNMT (which has been shown to be multifunctional) and B[ a ]P are involved in the induction of CYP1A1 and of GNMT as a potential role in the modulation of hypoxia inducible factor-1 function [ 32 , 33 ]. Previous work demonstrated the interaction of GNMT with DEPTOR, a mTORC1 binding protein overexpressed in HCC [34] .…”

Chronic Kidney Disease Induces Proarrhythmic Remodeling

“…Interestingly, we also observed that 13 of the 25 most significant DEGs in our sample were previously implicated in cellular response to hypoxia (Apln, Egln3, Eif4ebp1, Fmo2, Gnmt, Lrrc55, Mr1, Mycn, Nqo1, Nt5e, P4ha1, Prps1, and Trnp1; Figure 5A). [30][31][32][33][34][35][36][37][38][39][40][41][42][43] Of these 13 hypoxiarelated genes, 10 shared a connection to the well-known HIF (hypoxia-inducible factor) pathway (Apln, Egln3, Eif4ebp1, Fmo2, Gnmt, Lrrc55, Mycn, Nqo1, Nt5e, and P4ha1). [30][31][32][33]35,36,[38][39][40]42 A subset of these HIF-related transcripts are illustrated in Figure 5B.…”

“…[30][31][32][33][34][35][36][37][38][39][40][41][42][43] Of these 13 hypoxiarelated genes, 10 shared a connection to the well-known HIF (hypoxia-inducible factor) pathway (Apln, Egln3, Eif4ebp1, Fmo2, Gnmt, Lrrc55, Mycn, Nqo1, Nt5e, and P4ha1). [30][31][32][33]35,36,[38][39][40]42 A subset of these HIF-related transcripts are illustrated in Figure 5B. RBM3 and CIRP have known roles in physiologic stress response.…”

Mammalian Sulfur Amino Acid Metabolism: A Nexus Between Redox Regulation, Nutrition, Epigenetics, and Detoxification

“…Elimination of this interaction is probably a main contributor to HCC in Gnmt -/null mice. GNMT, as the PAH receptor, interacts with the aryl hydrocarbon receptor nuclear translocator (ARNT/HIF-1b) in CHO cells (349). However, upon binding of benzo(a)pyrene, GNMT dissociates from this oligomer and translocates to the nucleus for the activation of an XRE in the CYP1A1 promoter.…”