Molecular Endocrinology, Vol 9, 171-177, Copyright © 1995 by Endocrine Society

ARTICLES

In vivo growth hormone treatment rapidly stimulates the tyrosine phosphorylation and activation of Stat3

AM Gronowski, Z Zhong, Z Wen, MJ Thomas, JE Darnell Jr and P Rotwein
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

The mechanisms by which GH regulates gene expression to alter growth and metabolism are unknown. We have demonstrated previously that in vivo GH treatment rapidly stimulates the tyrosine phosphorylation of multiple nuclear proteins and have identified the inducible transcription factor Stat1 (formerly Stat91) as one of the major GH- activated nuclear phosphoproteins. We now show that Stat3, a new member of the STAT (signal transducer and activator of transcription) family of transcription factors, is also phosphorylated on tyrosine residues and rapidly appears in the nucleus in response to GH. Activated Stat3 interacts with the naturally occurring c-sis-inducible element of the c- fos gene after GH treatment, as demonstrated by gel mobility shift assay, and is a component of gel-shifted bands A and B when the high affinity sis-inducible element is used as a probe. Our results suggest that multiple STAT proteins may mediate some of the pleiotropic effects of GH on gene expression.

This article has been cited by other articles:

				T. X. Cui, R. Kwok, and J. Schwartz Cooperative regulation of endogenous cAMP-response element binding protein and CCAAT/enhancer-binding protein in GH-stimulated c-fos expression J. Endocrinol., January 1, 2008; 196(1): 89 - 100. [Abstract] [Full Text] [PDF]

				N. Masumoto, C. Tateno, A. Tachibana, R. Utoh, Y. Morikawa, T. Shimada, H. Momisako, T. Itamoto, T. Asahara, and K. Yoshizato GH enhances proliferation of human hepatocytes grafted into immunodeficient mice with damaged liver J. Endocrinol., September 1, 2007; 194(3): 529 - 537. [Abstract] [Full Text] [PDF]

				T. X. Cui, G. Piwien-Pilipuk, J. S. Huo, J. Kaplani, R. Kwok, and J. Schwartz Endogenous CCAAT/Enhancer Binding Protein {beta} and p300 Are Both Regulated by Growth Hormone to Mediate Transcriptional Activation Mol. Endocrinol., August 1, 2005; 19(8): 2175 - 2186. [Abstract] [Full Text] [PDF]

				M. Endo, Y. Takahashi, Y. Sasaki, T. Saito, and T. Kamataki Novel Gender-Related Regulation of CYP2C12 Gene Expression in Rats Mol. Endocrinol., May 1, 2005; 19(5): 1181 - 1190. [Abstract] [Full Text] [PDF]

				J. Woelfle and P. Rotwein In vivo regulation of growth hormone-stimulated gene transcription by STAT5b Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E393 - E401. [Abstract] [Full Text] [PDF]

				L. Q. Hong-Brown, C. R. Brown, R. N. Cooney, R. A. Frost, and C. H. Lang Sepsis-induced muscle growth hormone resistance occurs independently of STAT5 phosphorylation Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E63 - E72. [Abstract] [Full Text] [PDF]

				J. Woelfle, J. Billiard, and P. Rotwein Acute Control of Insulin-like Growth Factor-I Gene Transcription by Growth Hormone through Stat5b J. Biol. Chem., June 13, 2003; 278(25): 22696 - 22702. [Abstract] [Full Text] [PDF]

				E. Yang, L. Lerner, D. Besser, and J. E. Darnell Jr. Independent and Cooperative Activation of Chromosomal c-fos Promoter by STAT3 J. Biol. Chem., April 25, 2003; 278(18): 15794 - 15799. [Abstract] [Full Text] [PDF]

				S. G. Ronn, J. A. Hansen, K. Lindberg, A. E. Karlsen, and N. Billestrup The Effect of Suppressor of Cytokine Signaling 3 on GH Signaling in {beta}-Cells Mol. Endocrinol., September 1, 2002; 16(9): 2124 - 2134. [Abstract] [Full Text] [PDF]

				R. A. Frost, G. J. Nystrom, and C. H. Lang Regulation of IGF-I mRNA and Signal Transducers and Activators of Transcription-3 and -5 (Stat-3 and -5) by GH in C2C12 Myoblasts Endocrinology, February 1, 2002; 143(2): 492 - 503. [Abstract] [Full Text] [PDF]

				J. M. Bugni, T. M. Poole, and N. R. Drinkwater The little mutation suppresses DEN-induced hepatocarcinogenesis in mice and abrogates genetic and hormonal modulation of susceptibility Carcinogenesis, November 1, 2001; 22(11): 1853 - 1862. [Abstract] [Full Text] [PDF]

				H. W. Davey, T. Xie, M. J. McLachlan, R. J. Wilkins, D. J. Waxman, and D. R. Grattan STAT5b Is Required for GH-Induced Liver Igf-I Gene Expression Endocrinology, September 1, 2001; 142(9): 3836 - 3841. [Abstract] [Full Text] [PDF]

				L. N. N. Shoba, M. Newman, W. Liu, and W. L. Lowe Jr. LY 294002, an Inhibitor of Phosphatidylinositol 3-Kinase, Inhibits GH-Mediated Expression of the IGF-I Gene in Rat Hepatocytes Endocrinology, September 1, 2001; 142(9): 3980 - 3986. [Abstract] [Full Text] [PDF]

				P. L. Bergad, S. J. Schwarzenberg, J. T. Humbert, M. Morrison, S. Amarasinghe, H. C. Towle, and S. A. Berry Inhibition of growth hormone action in models of inflammation Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1906 - C1917. [Abstract] [Full Text] [PDF]

				P. L. Bergad, H. C. Towle, and S. A. Berry Yin-yang 1 and Glucocorticoid Receptor Participate in the Stat5-mediated Growth Hormone Response of the Serine Protease Inhibitor 2.1 Gene J. Biol. Chem., March 10, 2000; 275(11): 8114 - 8120. [Abstract] [Full Text] [PDF]

				L. Rui, S. F. Archer, L. S. Argetsinger, and C. Carter-Su Platelet-derived Growth Factor and Lysophosphatidic Acid Inhibit Growth Hormone Binding and Signaling via a Protein Kinase C-dependent Pathway J. Biol. Chem., January 28, 2000; 275(4): 2885 - 2892. [Abstract] [Full Text] [PDF]

				Y. Sasaki, Y. Takahashi, K. Nakayama, and T. Kamataki Cooperative Regulation of CYP2C12 Gene Expression by STAT5 and Liver-specific Factors in Female Rats J. Biol. Chem., December 24, 1999; 274(52): 37117 - 37124. [Abstract] [Full Text] [PDF]

				J. Liao, G. Piwien-Pilipuk, S. E. Ross, C. L. Hodge, L. Sealy, O. A. MacDougald, and J. Schwartz CCAAT/Enhancer-binding Protein beta (C/EBPbeta ) and C/EBPdelta Contribute to Growth Hormone-regulated Transcription of c-fos J. Biol. Chem., October 29, 1999; 274(44): 31597 - 31604. [Abstract] [Full Text] [PDF]

				P. Tollet-Egnell, A. Flores-Morales, A. Stavréus-Evers, L. Sahlin, and G. Norstedt Growth Hormone Regulation of SOCS-2, SOCS-3, and CIS Messenger Ribonucleic Acid Expression in the Rat Endocrinology, August 1, 1999; 140(8): 3693 - 3704. [Abstract] [Full Text]

				C. Benbassat, L. N. N. Shoba, M. Newman, M. L. Adamo, S. J. Frank, and W. L. Lowe Jr. Growth Hormone-Mediated Regulation of Insulin-Like Growth Factor I Promoter Activity in C6 Glioma Cells Endocrinology, July 1, 1999; 140(7): 3073 - 3081. [Abstract] [Full Text]

				L. Rui and C. Carter-Su Identification of SH2-Bbeta as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2 PNAS, June 22, 1999; 96(13): 7172 - 7177. [Abstract] [Full Text] [PDF]

				S. A. Berry, P. L. Bergad, A. M. Stolz, H. C. Towle, and S. J. Schwarzenberg Regulation of Spi 2.1 and 2.2 gene expression after turpentine inflammation: discordant responses to IL-6 Am J Physiol Cell Physiol, June 1, 1999; 276(6): C1374 - C1382. [Abstract] [Full Text] [PDF]

				P. M. Piatti, L. D. Monti, A. Caumo, M. Conti, F. Magni, M. Galli-Kienle, E. Fochesato, A. Pizzini, L. Baldi, G. Valsecchi, et al. Mediation of the Hepatic Effects of Growth Hormone by Its Lipolytic Activity J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1658 - 1663. [Abstract] [Full Text]

				L. Liang, T. Zhou, J. Jiang, J. H. Pierce, T. A. Gustafson, and S. J. Frank Insulin Receptor Substrate-1 Enhances Growth Hormone-Induced Proliferation Endocrinology, May 1, 1999; 140(5): 1972 - 1983. [Abstract] [Full Text]

				C. Rusterholz, P. C. Henrioud, and M. Nabholz Interleukin-2 (IL-2) Regulates the Accessibility of the IL-2-Responsive Enhancer in the IL-2 Receptor alpha  Gene to Transcription Factors Mol. Cell. Biol., April 1, 1999; 19(4): 2681 - 2689. [Abstract] [Full Text] [PDF]

				C. A. Gebert, S.-H. Park, and D. J. Waxman Termination of Growth Hormone Pulse-Induced STAT5b Signaling Mol. Endocrinol., January 1, 1999; 13(1): 38 - 56. [Abstract] [Full Text]

				A. Chakraborty, K. F. Dyer, M. Cascio, T. A. Mietzner, and D. J. Tweardy Identification of a Novel Stat3 Recruitment and Activation Motif Within the Granulocyte Colony-Stimulating Factor Receptor Blood, January 1, 1999; 93(1): 15 - 24. [Abstract] [Full Text] [PDF]

				C. Hodge, J. Liao, M. Stofega, K. Guan, C. Carter-Su, and J. Schwartz Growth Hormone Stimulates Phosphorylation and Activation of Elk-1 and Expression of c-fos, egr-1, and junB through Activation of Extracellular Signal-regulated Kinases 1 and 2 J. Biol. Chem., November 20, 1998; 273(47): 31327 - 31336. [Abstract] [Full Text] [PDF]

				G. T. Ooi, K. R. Hurst, M. N. Poy, M. M. Rechler, and Y. R. Boisclair Binding of STAT5a and STAT5b to a Single Element Resembling a {gamma}-Interferon-Activated Sequence Mediates the Growth Hormone Induction of the Mouse Acid-Labile Subunit Promoter in Liver Cells Mol. Endocrinol., May 1, 1998; 12(5): 675 - 687. [Abstract] [Full Text]

				T.-W. L. Gong, D. J. Meyer, J. Liao, C. L. Hodge, G. S. Campbell, X. Wang, N. Billestrup, C. Carter-Su, and J. Schwartz Regulation of Glucose Transport and c-fos and egr-1 Expression in Cells with Mutated or Endogenous Growth Hormone Receptors Endocrinology, April 1, 1998; 139(4): 1863 - 1871. [Abstract] [Full Text] [PDF]

				A. E. Simar-Blanchet, C. Legraverend, J. P. Thissen, and A. Le Cam Transcription of the Rat Serine Protease Inhibitor 2.1 Gene in Vivo: Correlation with GAGA Box Promoter Occupancy and Mechanism of Cytokine-Mediated Down-Regulation Mol. Endocrinol., March 1, 1998; 12(3): 391 - 404. [Abstract] [Full Text]

				C. Le Stunff and P. Rotwein Growth Hormone Stimulates Interferon Regulatory Factor-1 Gene Expression in the Liver Endocrinology, March 1, 1998; 139(3): 859 - 866. [Abstract] [Full Text] [PDF]

				C. Ohlsson, B.-A. Bengtsson, O. G. P. Isaksson, T. T. Andreassen, and M. C. Slootweg Growth Hormone and Bone Endocr. Rev., February 1, 1998; 19(1): 55 - 79. [Abstract] [Full Text]

				S.-O. Kim, J. Jiang, W. Yi, G.-S. Feng, and S. J. Frank Involvement of the Src Homology 2-containing Tyrosine Phosphatase SHP-2 in Growth Hormone Signaling J. Biol. Chem., January 23, 1998; 273(4): 2344 - 2354. [Abstract] [Full Text] [PDF]

				J. S. Freeth, C. M. Silva, A. J. Whatmore, and P. E. Clayton Activation of the Signal Transducers and Activators of Transcription Signaling Pathway by Growth Hormone (GH) in Skin Fibroblasts from Normal and GH Binding Protein-Positive Laron Syndrome Children Endocrinology, January 1, 1998; 139(1): 20 - 28. [Abstract] [Full Text] [PDF]

				L. S. Smit, J. A. VanderKuur, A. Stimage, Y. Han, G. Luo, L.-y. Yu-Lee, J. Schwartz, and C. Carter-Su Growth Hormone-Induced Tyrosyl Phosphorylation and Deoxyribonucleic Acid Binding Activity of Stat5A and Stat5B Endocrinology, August 1, 1997; 138(8): 3426 - 3434. [Abstract] [Full Text] [PDF]

				P. A. Ram and D. J. Waxman Interaction of Growth Hormone-activated STATs with SH2-containing Phosphotyrosine Phosphatase SHP-1 and Nuclear JAK2 Tyrosine Kinase J. Biol. Chem., July 11, 1997; 272(28): 17694 - 17702. [Abstract] [Full Text] [PDF]

				G. B. Udy, R. P. Towers, R. G. Snell, R. J. Wilkins, S.-H. Park, P. A. Ram, D. J. Waxman, and H. W. Davey Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression PNAS, July 8, 1997; 94(14): 7239 - 7244. [Abstract] [Full Text] [PDF]

				C. A. Gebert, S.-H. Park, and D. J. Waxman Regulation of Signal Transducer and Activator of Transcription (STAT) 5b Activation by the Temporal Pattern of Growth Hormone Stimulation Mol. Endocrinol., April 1, 1997; 11(4): 400 - 414. [Abstract] [Full Text]

				D. J. Waxman, S. Zhao, and H. K. Choi Interaction of a Novel Sex-dependent, Growth Hormone-regulated Liver Nuclear Factor with CYP2C12 Promoter J. Biol. Chem., November 22, 1996; 271(47): 29978 - 29987. [Abstract] [Full Text] [PDF]

				P. A. Ram, S.-H. Park, H. K. Choi, and D. J. Waxman Growth Hormone Activation of Stat 1, Stat 3, and Stat 5 in Rat Liver J. Biol. Chem., March 8, 1996; 271(10): 5929 - 5940. [Abstract] [Full Text] [PDF]

				Y. Takahashi, H. Kaji, Y. Okimura, K. Goji, H. Abe, and K. Chihara Short Stature Caused by a Mutant Growth Hormone N. Engl. J. Med., February 15, 1996; 334(7): 432 - 436. [Full Text] [PDF]

				P. L. Bergad, H.-M. Shih, H. C. Towle, S. J. Schwarzenberg, and S. A. Berry Growth Hormone Induction of Hepatic Serine Protease Inhibitor 2.1 Transcription Is Mediated by a Stat5-related Factor Binding Synergistically to Two [IMAGE]-Activated Sites J. Biol. Chem., October 20, 1995; 270(42): 24903 - 24910. [Abstract] [Full Text] [PDF]