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Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Dr. David J. Waxman, Department of Biology, Boston University, 5 Cummington Street, Boston, Massachusetts 02215. E-mail: djw{at}bio.bu.edu
STAT5b, a member of the signal transducers and activators of transcription family, is activated in rat liver in response to the intermittent (pulsatile) plasma pattern of GH that is characteristic of adult males. Previous studies have shown that the near-continuous plasma GH pattern of adult female rats is associated with a dramatic down-regulation of the STAT5 activation pathway. The present study demonstrates the presence of a low-level STAT5 DNA-binding activity in adult female rat liver and investigates the hormonal factors required for its maintenance. PRL is not responsible for this low-level STAT5 activity, as demonstrated in experiments involving estrus cycle monitoring (to investigate a possible role of the proestrus PRL surge), implantation of bromocriptine pellets (to eliminate PRL release by the pituitary), and direct injection of purified PRL. Rather, the low-level STAT5 activity is shown to result from chronic plasma GH stimulation, as demonstrated by GH infusion studies carried out in hypophysectomized rats. Furthermore, gel mobility supershift experiments demonstrate that the same STAT5-containing DNA-binding complexes are formed by both male and female adult rat liver extracts, albeit at approximately 10- to 20-fold lower levels by the female extracts. This DNA-binding activity is primarily comprised of STAT5b but also contains STAT5a, which is shown to be preferentially activated by the male plasma GH pattern in a manner similar to STAT5b. Thus, the dominance of activated STAT5b, compared with STAT5a, in the strong DNA-binding complexes formed in adult male rat liver nuclear extracts, is a reflection of the relative abundance in liver of the two STAT5 forms and is not attributable to an intrinsic, preferential activation of STAT5b by plasma GH pulses. The physiological significance of the low-level activated STAT5a and STAT5b seen in female rat liver and its effects on liver gene expression are uncertain but may involve the activation of female-expressed cytochromes P450 and other liver genes.
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P. A. Ram and D. J. Waxman SOCS/CIS Protein Inhibition of Growth Hormone-stimulated STAT5 Signaling by Multiple Mechanisms J. Biol. Chem., December 10, 1999; 274(50): 35553 - 35561. [Abstract] [Full Text] [PDF]
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N. Delesque-Touchard, S.-H. Park, and D. J. Waxman Synergistic Action of Hepatocyte Nuclear Factors 3 and 6 on CYP2C12 Gene Expression and Suppression by Growth Hormone-activated STAT5b. PROPOSED MODEL FOR FEMALE-SPECIFIC EXPRESSION OF CYP2C12 IN ADULT RAT LIVER J. Biol. Chem., October 27, 2000; 275(44): 34173 - 34182. [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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