Involvement of transcription factor HNF3gamma in the effect of o-aminoazotoluene on glucocorticoid induction of tyrosine aminotransferase in mice sensitive to its hepatocarcinogenic action.
In the rodent liver, hepatocarcinogens inhibit the glucocorticoid induction of several liver-specific genes, including tyrosine aminotransferase (TAT). A distinct positive correlation exists in mice between the extent of inhibition of TAT induction after acute administration of o-aminoazotoluene (OAT) and the frequency of liver tumors after chronic exposure to the carcinogen. To elucidate the mechanism of the carcinogenic action, the effects of OAT on the DNA-binding activity of several transcription factors participating in the glucocorticoid regulation of TAT gene expression were studied. The experimental inbred male mice were sensitive (A/He and SWR/J, tumor induction frequency of 75-100%, TAT induction inhibition of 35-50%) and resistant (CC57BR/Mv and AKR/J, 0-6% and 10-15%, respectively) to OAT. Gel retardation experiments showed that hepatocyte nuclear factor 3 (HNF3)gamma DNA-binding activity was strongly reduced in nuclear extracts from the livers of OAT-treated A/He and SWR/J mice but only slightly reduced in CC57Br/Mv and AKR/J mice. The DNA-binding activities of Ets, AP1 family members, and GME binding proteins were unaffected. HNF3gamma DNA-binding activity was reduced by 1 h after OAT administration and remained low for 1 mo, as did inhibition of TAT induction in the liver. These results suggested that the inhibitory effect of OAT on the glucocorticoid induction of TAT is mediated by reduced HNF3gamma DNA-binding activity.
Kropachev
K Y
KY
Laboratory of Gene Expression Control, Institute of Cytology and Genetics of the Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia.
Kaledin
V I
VI
Kobzev
V F
VF
Plisov
S Y
SY
Levashova
Z B
ZB
Merkulova
T I
TI
D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D051543:Hepatocyte Nuclear Factor 3-gamma; D006854:Hydrocortisone / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D009687:Nuclear Proteins / Q000378:metabolism*; D013045:Species Specificity; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014444:Tyrosine Transaminase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009762:o-Aminoazotoluene / Q000494:pharmacology*
D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C496506:Foxa3 protein, mouse; D005938:Glucocorticoids; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051543:Hepatocyte Nuclear Factor 3-gamma; D014444:Tyrosine Transaminase; D009762:o-Aminoazotoluene; D006854:Hydrocortisone