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Division of Cell and Molecular Biology Department of Biology Boston University Boston, Massachusetts 02215
Plasma GH profiles, intermittent in adult male and
continuous in adult female rats, respectively, activate unique patterns
of gene transcription in male and female rat liver. Pulsatile, but not
continuous, GH exposure activates liver STAT5 (signal transducer and
activator of transcription-5) by tyrosine phosphorylation, leading to
nuclear translocation, and is proposed to play a key role in GH
pulse-regulated male-specific liver gene expression. The mechanisms
underlying the GH pattern dependence of STAT5 activation are presently
investigated using a rat hepatocyte-derived cell line. Rat GH
stimulated tyrosine phosphorylation followed by serine or threonine
phosphorylation, leading to activation of the DNA-binding activity of
STAT5b, the major STAT5 form present in these cells. Maximal STAT5b
activation required a full 20 min at a receptor-saturating GH
concentration of 50 ng/ml, suggesting that hormone binding leading to
receptor dimerization is a relatively slow process. Repeat cycles of GH
pulsation led to repeat cycles of STAT5b activation followed by
deactivation, similar to rat liver in vivo. Full
responsiveness to succeeding GH pulses required a minimum GH off-time
of 
2.5 h, but was independent of new protein synthesis.
Continuous GH exposure led to down-regulation of activated STAT5b,
consistent with the desensitization of this GH pulse-activated pathway
observed in female rat liver. The rapid deactivation of STAT5b after
termination of a GH pulse involved phosphotyrosine dephosphorylation as
a key first step and could be blocked by pervanadate, a phosphotyrosine
phosphatase inhibitor. Unexpectedly, serine/threonine kinase inhibitors
also inhibited STAT5b deactivation. These studies establish that STAT5b
is responsive to the temporal pattern of GH stimulation and demonstrate
a role for both a tyrosine phosphatase and a serine/threonine kinase in
resetting this JAK/STAT signaling apparatus so that it may respond to
subsequent rounds of GH pulse activation.
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Y.-C. Zhou and D. J. Waxman Cross-talk between Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) and Peroxisome Proliferator-activated Receptor-alpha (PPARalpha ) Signaling Pathways. GROWTH HORMONE INHIBITION OF PPARalpha TRANSCRIPTIONAL ACTIVITY MEDIATED BY STAT5b J. Biol. Chem., January 29, 1999; 274(5): 2672 - 2681. [Abstract] [Full Text] [PDF]
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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]
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C. Buggs, N. Nasrin, A. Mode, P. Tollet, H.-F. Zhao, J.-A. Gustafsson, and M. Alexander-Bridges IRE-ABP (Insulin Response Element-A Binding Protein), an SRY-Like Protein, Inhibits C/EBP{alpha} (CCAAT/Enhancer-Binding Protein {alpha})-Stimulated Expression of the Sex-Specific Cytochrome P450 2C12 Gene Mol. Endocrinol., September 1, 1998; 12(9): 1294 - 1309. [Abstract] [Full Text]
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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]
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M. Kanzaki and P. L. Morris Lactogenic Hormone-Inducible Phosphorylation and Gamma-Activated Site-Binding Activities of Stat5b in Primary Rat Leydig Cells and MA-10 Mouse Leydig Tumor Cells Endocrinology, April 1, 1998; 139(4): 1872 - 1882. [Abstract] [Full Text] [PDF]
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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]
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Y. Wang, O. Robledo, E. Kinzie, F. Blanchard, C. Richards, A. Miyajima, and H. Baumann Receptor Subunit-specific Action of Oncostatin M in Hepatic Cells and Its Modulation by Leukemia Inhibitory Factor J. Biol. Chem., August 11, 2000; 275(33): 25273 - 25285. [Abstract] [Full Text] [PDF]
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P. A. Ram and D. J. Waxman Role of the Cytokine-inducible SH2 Protein CIS in Desensitization of STAT5b Signaling by Continuous Growth Hormone J. Biol. Chem., December 8, 2000; 275(50): 39487 - 39496. [Abstract] [Full Text] [PDF]
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P. M. Gowri, T. C. Ganguly, J. Cao, M. N. Devalaraja, B. Groner, and M. Vore Conversion of Threonine 757 to Valine Enhances Stat5a Transactivation Potential J. Biol. Chem., March 23, 2001; 276(13): 10485 - 10491. [Abstract] [Full Text] [PDF]
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