This Article Full Text Full Text (PDF) All Versions of this Article: 20/3/647    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Holloway, M. G. Articles by Waxman, D. J. Search for Related Content PubMed PubMed Citation Articles by Holloway, M. G. Articles by Waxman, D. J.

Codependence of Growth Hormone-Responsive, Sexually Dimorphic Hepatic Gene Expression on Signal Transducer and Activator of Transcription 5b and Hepatic Nuclear Factor 4

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}bu.edu.

Targeted disruption of the signal transducer and activator of transcription 5b gene (STAT5b) leads to decreased expression in male mouse liver of a male-predominant cytochrome (Cyp) 2d protein, whereas female-predominant Cyp2b proteins are increased. Presently, we characterize the effects of STAT5b deficiency on 15 specific, individual Cyp RNAs and other sexually dimorphic liver gene products. All seven male-specific RNAs investigated were decreased to normal female levels in STAT5b-deficient male liver, whereas five of eight female-specific RNAs, designated class I female genes, were increased in expression up to 200-fold or more. STAT5b deficiency had a much more modest effect on the expression of these genes in females. Hypophysectomy and GH replacement studies demonstrated positive GH pulse regulation of all seven male RNAs and negative GH pulse regulation of class I, but not class II, female RNAs in wild-type, but not in STAT5b-deficient, male mice. A majority of the sex-specific genes responded in parallel to the loss of STAT5b and the loss of hepatocyte nuclear factor 4, indicating that both transcription factors are essential and suggesting they may coregulate sexually dimorphic liver gene expression. Continuous GH treatment of intact male mice, which overrides the endogenous male, pulsatile plasma GH pattern, down-regulated all seven male RNAs and induced expression of the five class I female RNAs within 4–7 d; however, induction of class II female RNAs was delayed until d 7–14. Given the slow responses of all 15 genes to changes in plasma GH status, GH regulation of sex-specific Cyp expression is proposed to be indirect and mediated by STAT5b- and hepatocyte nuclear factor 4-dependent factors that may include repressors of female-specific Cyps and other targets of GH action.

NURSA Molecule Pages Link:

Nuclear Receptors:   HNF4α

This article has been cited by other articles:

				T. Hashita, T. Sakuma, M. Akada, A. Nakajima, H. Yamahara, S. Ito, H. Takesako, and N. Nemoto Forkhead Box A2-Mediated Regulation of Female-Predominant Expression of the Mouse Cyp2b9 Gene Drug Metab. Dispos., June 1, 2008; 36(6): 1080 - 1087. [Abstract] [Full Text] [PDF]

				T. Sakuma, W. Bhadhprasit, T. Hashita, and N. Nemoto Synergism of Glucocorticoid Hormone with Growth Hormone for Female-Specific Mouse Cyp3a44 Gene Expression Drug Metab. Dispos., May 1, 2008; 36(5): 878 - 884. [Abstract] [Full Text] [PDF]

				M. G. Holloway, G. D. Miles, A. A. Dombkowski, and D. J. Waxman Liver-Specific Hepatocyte Nuclear Factor-4{alpha} Deficiency: Greater Impact on Gene Expression in Male than in Female Mouse Liver Mol. Endocrinol., May 1, 2008; 22(5): 1274 - 1286. [Abstract] [Full Text] [PDF]

				K. H. Clodfelter, G. D. Miles, V. Wauthier, M. G. Holloway, X. Zhang, P. Hodor, W. J. Ray, and D. J. Waxman Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis Physiol Genomics, September 11, 2007; 31(1): 63 - 74. [Abstract] [Full Text] [PDF]

				E. V. Laz, M. G. Holloway, C.-S. Chen, and D. J. Waxman Characterization of Three Growth Hormone-Responsive Transcription Factors Preferentially Expressed in Adult Female Liver Endocrinology, July 1, 2007; 148(7): 3327 - 3337. [Abstract] [Full Text] [PDF]

				M. G. Holloway, Y. Cui, E. V. Laz, A. Hosui, L. Hennighausen, and D. J. Waxman Loss of Sexually Dimorphic Liver Gene Expression upon Hepatocyte-Specific Deletion of Stat5a-Stat5b Locus Endocrinology, May 1, 2007; 148(5): 1977 - 1986. [Abstract] [Full Text] [PDF]

				O. M. Vidal, R. Merino, E. Rico-Bautista, L. Fernandez-Perez, D. J. Chia, J. Woelfle, M. Ono, B. Lenhard, G. Norstedt, P. Rotwein, et al. In Vivo Transcript Profiling and Phylogenetic Analysis Identifies Suppressor of Cytokine Signaling 2 as a Direct Signal Transducer and Activator of Transcription 5b Target in Liver Mol. Endocrinol., January 1, 2007; 21(1): 293 - 311. [Abstract] [Full Text] [PDF]

				D. J. Waxman and C. O'Connor Growth Hormone Regulation of Sex-Dependent Liver Gene Expression Mol. Endocrinol., November 1, 2006; 20(11): 2613 - 2629. [Abstract] [Full Text] [PDF]

				K. H. Clodfelter, M. G. Holloway, P. Hodor, S.-H. Park, W. J. Ray, and D. J. Waxman 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., June 1, 2006; 20(6): 1333 - 1351. [Abstract] [Full Text] [PDF]