Direct Glucocorticoid Receptor-Stat5 Interaction in Hepatocytes Controls Body Size and Maturation-related Gene Expression

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2007 May 17

PMID 17504935

Citations 62

Authors

David Engblom

Jan-Wilhelm Kornfeld

Lukas Schwake

Francois Tronche

Andreas Reimann

Hartmut Beug

Lothar Hennighausen

Richard Moriggl

Gunther Schutz

Affiliations

Soon will be listed here.

Abstract

The glucocorticoid receptor regulates transcription through DNA binding as well as through cross-talk with other transcription factors. In hepatocytes, the glucocorticoid receptor is critical for normal postnatal growth. Using hepatocyte-specific and domain-selective mutations in the mouse we show that Stat5 in hepatocytes is essential for normal postnatal growth and that it mediates the growth-promoting effect of the glucocorticoid receptor through a direct interaction involving the N-terminal tetramerization domain of Stat5b. This interaction mediates a selective and unexpectedly extensive part of the transcriptional actions of these molecules since it controls the expression of gene sets involved in growth and sexual maturation.

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References

Teglund S, Mckay C, Schuetz E, Van Deursen J, Stravopodis D, Wang D . Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell. 1998; 93(5):841-50. DOI: 10.1016/s0092-8674(00)81444-0. View

Reichardt H, Kaestner K, Tuckermann J, Kretz O, Wessely O, Bock R . DNA binding of the glucocorticoid receptor is not essential for survival. Cell. 1998; 93(4):531-41. DOI: 10.1016/s0092-8674(00)81183-6. View

Yakar S, Liu J, STANNARD B, Butler A, Accili D, Sauer B . Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999; 96(13):7324-9. PMC: 22084. DOI: 10.1073/pnas.96.13.7324. View

Rowland J, Lichanska A, Kerr L, White M, dAniello E, Maher S . In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. Mol Cell Biol. 2004; 25(1):66-77. PMC: 538772. DOI: 10.1128/MCB.25.1.66-77.2005. View

Moriggl R, Sexl V, Kenner L, Duntsch C, Stangl K, Gingras S . Stat5 tetramer formation is associated with leukemogenesis. Cancer Cell. 2005; 7(1):87-99. DOI: 10.1016/j.ccr.2004.12.010. View

Yao Z, Cui Y, Watford W, Bream J, Yamaoka K, Hissong B . Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci U S A. 2006; 103(4):1000-5. PMC: 1327727. DOI: 10.1073/pnas.0507350103. View

Clodfelter K, Holloway M, Hodor P, Park S, Ray W, Waxman D . Sex-dependent liver gene expression is extensive and largely dependent upon signal transducer and activator of transcription 5b (STAT5b): STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis. Mol Endocrinol. 2006; 20(6):1333-51. DOI: 10.1210/me.2005-0489. View

Hoelbl A, Kovacic B, Kerenyi M, Simma O, Warsch W, Cui Y . Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation. Blood. 2006; 107(12):4898-906. PMC: 2875852. DOI: 10.1182/blood-2005-09-3596. View

Klover P, Hennighausen L . Postnatal body growth is dependent on the transcription factors signal transducers and activators of transcription 5a/b in muscle: a role for autocrine/paracrine insulin-like growth factor I. Endocrinology. 2006; 148(4):1489-97. DOI: 10.1210/en.2006-1431. View

10.

Kellendonk C, Opherk C, Anlag K, Schutz G, Tronche F . Hepatocyte-specific expression of Cre recombinase. Genesis. 2000; 26(2):151-3. DOI: 10.1002/(sici)1526-968x(200002)26:2<151::aid-gene17>3.0.co;2-e. View

11.

Biola A, Lefebvre P, Perrin-Wolff M, Sturm M, Bertoglio J, Pallardy M . Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1. Mol Endocrinol. 2001; 15(7):1062-76. DOI: 10.1210/mend.15.7.0657. View

12.

Reichardt H, Tuckermann J, Gottlicher M, Vujic M, Weih F, Angel P . Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J. 2001; 20(24):7168-73. PMC: 125338. DOI: 10.1093/emboj/20.24.7168. View

13.

Yakar S, Rosen C, Beamer W, Ackert-Bicknell C, Wu Y, Liu J . Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002; 110(6):771-81. PMC: 151128. DOI: 10.1172/JCI15463. View

14.

Doniger S, Salomonis N, Dahlquist K, Vranizan K, Lawlor S, Conklin B . MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data. Genome Biol. 2003; 4(1):R7. PMC: 151291. DOI: 10.1186/gb-2003-4-1-r7. View

15.

Tronche F, Opherk C, Moriggl R, Kellendonk C, Reimann A, Schwake L . Glucocorticoid receptor function in hepatocytes is essential to promote postnatal body growth. Genes Dev. 2004; 18(5):492-7. PMC: 374231. DOI: 10.1101/gad.284704. View

16.

Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng C . Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol. 2004; 24(18):8037-47. PMC: 515028. DOI: 10.1128/MCB.24.18.8037-8047.2004. View

17.

Isaksson O, Jansson J, Gause I . Growth hormone stimulates longitudinal bone growth directly. Science. 1982; 216(4551):1237-9. DOI: 10.1126/science.7079756. View

18.

Chin E, Zhou J, Dai J, BAXTER R, Bondy C . Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complex. Endocrinology. 1994; 134(6):2498-504. DOI: 10.1210/endo.134.6.7515002. View

19.

Moriggl R, Gouilleux-Gruart V, Jahne R, Berchtold S, Gartmann C, Liu X . Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol Cell Biol. 1996; 16(10):5691-700. PMC: 231569. DOI: 10.1128/MCB.16.10.5691. View

20.

Stocklin E, Wissler M, Gouilleux F, Groner B . Functional interactions between Stat5 and the glucocorticoid receptor. Nature. 1996; 383(6602):726-8. DOI: 10.1038/383726a0. View