Expression of Hepatocyte Nuclear Factor 6 in Rat Liver is Sex-dependent and Regulated by Growth Hormone

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1997 Nov 14

PMID 9356445

Citations 24

Authors

O Lahuna

L Fernandez

H Karlsson

D Maiter

F P Lemaigre

G G Rousseau

J Gustafsson

A Mode

Affiliations

Soon will be listed here.

Abstract

Growth hormone (GH) binding to its receptor modulates gene transcription by influencing the amount or activity of transcription factors. In the rat, GH exerts sexually dimorphic effects on liver gene transcription through its pattern of secretion which is intermittent in males and continuous in females. The expression of the CYP2C12 gene coding for the female-specific cytochrome P450 2C12 protein is dependent on the continuous exposure to GH. To identify the transcription factor(s) that mediate(s) this sex-dependent GH effect, we studied the interactions of the CYP2C12 promoter with liver nuclear proteins obtained from male and female rats and from hypophysectomized animals treated or not by continuous GH infusion. GH treatment induced the binding of a protein that we identified as hepatocyte nuclear factor (HNF) 6, the prototype of a novel class of homeodomain transcription factors. HNF-6 competed with HNF-3 for binding to the same site in the CYP2C12 promoter. This HNF-6/HNF-3 binding site conveyed both HNF-6- and HNF-3-stimulated transcription of a reporter gene construct in transient cotransfection experiments. Electrophoretic mobility shift assays showed more HNF-6 DNA-binding activity in female than in male liver nuclear extracts. Liver HNF-6 mRNA was barely detectable in the hypophysectomized rats and was restored to normal levels by GH treatment. This work provides an example of a homeodomain-containing transcription factor that is GH-regulated and also reports on the hormonal regulation of HNF-6.

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References

Matsunaga T, Nomoto M, Kozak C, Gonzalez F . Structure and in vitro transcription of the rat CYP2A1 and CYP2A2 genes and regional localization of the CYP2A gene subfamily on mouse chromosome 7. Biochemistry. 1990; 29(5):1329-41. DOI: 10.1021/bi00457a032. View

Waxman D, Zhao S, Choi H . Interaction of a novel sex-dependent, growth hormone-regulated liver nuclear factor with CYP2C12 promoter. J Biol Chem. 1996; 271(47):29978-87. DOI: 10.1074/jbc.271.47.29978. View

Tollet P, Enberg B, Mode A . Growth hormone (GH) regulation of cytochrome P-450IIC12, insulin-like growth factor-I (IGF-I), and GH receptor messenger RNA expression in primary rat hepatocytes: a hormonal interplay with insulin, IGF-I, and thyroid hormone. Mol Endocrinol. 1990; 4(12):1934-42. DOI: 10.1210/mend-4-12-1934. View

Weigent D, Blalock J . Expression of growth hormone by lymphocytes. Int Rev Immunol. 1989; 4(3):193-211. DOI: 10.3109/08830188909054418. View

Slootweg M, de Groot R, HERRMANN-ERLEE M, Koornneef I, Kruijer W, Kramer Y . Growth hormone induces expression of c-jun and jun B oncogenes and employs a protein kinase C signal transduction pathway for the induction of c-fos oncogene expression. J Mol Endocrinol. 1991; 6(2):179-88. DOI: 10.1677/jme.0.0060179. View

Sundseth S, Alberta J, Waxman D . Sex-specific, growth hormone-regulated transcription of the cytochrome P450 2C11 and 2C12 genes. J Biol Chem. 1992; 267(6):3907-14. View

Legraverend C, Mode A, Westin S, Strom A, Eguchi H, Zaphiropoulos P . Transcriptional regulation of rat P-450 2C gene subfamily members by the sexually dimorphic pattern of growth hormone secretion. Mol Endocrinol. 1992; 6(2):259-66. DOI: 10.1210/mend.6.2.1569969. View

Liddle C, Mode A, Legraverend C, Gustafsson J . Constitutive expression and hormonal regulation of male sexually differentiated cytochromes P450 in primary cultured rat hepatocytes. Arch Biochem Biophys. 1992; 298(1):159-66. DOI: 10.1016/0003-9861(92)90107-8. View

Overdier D, Porcella A, Costa R . The DNA-binding specificity of the hepatocyte nuclear factor 3/forkhead domain is influenced by amino-acid residues adjacent to the recognition helix. Mol Cell Biol. 1994; 14(4):2755-66. PMC: 358641. DOI: 10.1128/mcb.14.4.2755-2766.1994. View

10.

Legraverend C, Eguchi H, Strom A, Lahuna O, Mode A, Tollet P . Transactivation of the rat CYP2C13 gene promoter involves HNF-1, HNF-3, and members of the orphan receptor subfamily. Biochemistry. 1994; 33(33):9889-97. DOI: 10.1021/bi00199a010. View

11.

Qian X, Samadani U, Porcella A, Costa R . Decreased expression of hepatocyte nuclear factor 3 alpha during the acute-phase response influences transthyretin gene transcription. Mol Cell Biol. 1995; 15(3):1364-76. PMC: 230360. DOI: 10.1128/MCB.15.3.1364. View

12.

Roux J, Pictet R, Grange T . Hepatocyte nuclear factor 3 determines the amplitude of the glucocorticoid response of the rat tyrosine aminotransferase gene. DNA Cell Biol. 1995; 14(5):385-96. DOI: 10.1089/dna.1995.14.385. View

13.

Clarkson R, Chen C, Harrison S, Wells C, Muscat G, Waters M . Early responses of trans-activating factors to growth hormone in preadipocytes: differential regulation of CCAAT enhancer-binding protein-beta (C/EBP beta) and C/EBP delta. Mol Endocrinol. 1995; 9(1):108-20. DOI: 10.1210/mend.9.1.7760844. View

14.

Tannenbaum G, Martin J . Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat. Endocrinology. 1976; 98(3):562-70. DOI: 10.1210/endo-98-3-562. View

15.

Eden S . Age- and sex-related differences in episodic growth hormone secretion in the rat. Endocrinology. 1979; 105(2):555-60. DOI: 10.1210/endo-105-2-555. View

16.

Chirgwin J, Przybyla A, MacDonald R, Rutter W . Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979; 18(24):5294-9. DOI: 10.1021/bi00591a005. View

17.

Norstedt G, Palmiter R . Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver. Cell. 1984; 36(4):805-12. DOI: 10.1016/0092-8674(84)90030-8. View

18.

Isaksson O, Eden S, Jansson J . Mode of action of pituitary growth hormone on target cells. Annu Rev Physiol. 1985; 47:483-99. DOI: 10.1146/annurev.ph.47.030185.002411. View

19.

Mathews L, Norstedt G, Palmiter R . Regulation of insulin-like growth factor I gene expression by growth hormone. Proc Natl Acad Sci U S A. 1986; 83(24):9343-7. PMC: 387134. DOI: 10.1073/pnas.83.24.9343. View

20.

Yoon J, Towle H, Seelig S . Growth hormone induces two mRNA species of the serine protease inhibitor gene family in rat liver. J Biol Chem. 1987; 262(9):4284-9. View