Aryl hydrocarbon receptor-mediated suppression of GH receptor and Janus kinase 2 expression in mice.
Differential mRNA display revealed that a cDNA encoding the major urinary protein 2 (MUP2) that belongs to the lipocalin superfamily was absent in livers of mice treated with 3-methylcholanthrene (MC). The expression of MUP2 is known to be stimulated by growth hormone (GH), through the GH receptor (GHR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signal transduction pathway. Since MC is an aryl hydrocarbon receptor (AhR) ligand, the effects of MC treatment on the expression of GHR, JAK2 or STAT5 in the livers of wild-type or AhR-null mice were examined. The result indicated that the expression of GHR and JAK2 mRNA was greatly decreased by MC in wild-type mice but not in AhR-null mice. In addition, the binding activity of STAT5 bound to STAT5-binding element was reduced after MC treatment in wild-type mice but not in AhR-null mice. Based on these results, we conclude that the suppression of MUP2 mRNA expression by MC is caused by the AhR-mediated disruption of the GH signaling pathway. Possible mechanism(s) by which exposure to aromatic hydrocarbons causes a decrease in the body weight of mice, which has been referred to as wasting syndrome, will also be discussed.
Nukaya
Manabu
M
Division of Pharmacobio-dynamics, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
Takahashi
Yoshiki
Y
Gonzalez
Frank J
FJ
Kamataki
Tetsuya
T
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D053614:Janus Kinase 2; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000187:drug effects / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D019282:Wasting Syndrome / Q000209:etiology
D002273:Carcinogens; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D008748:Methylcholanthrene; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2