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Nuclear Actions of Growth Hormone: An In Vivo Perspective¹

Departments of Biochemistry & Molecular Biophysics and Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110

Abstract

The growth-promoting effects of growth hormone (GH) in humans and animals are mediated by specific proteins whose genes are regulated by signal transduction pathways initiated by the binding of GH to its cell-surface receptor. Recent studies have defined the earliest steps in GH action, and have begun to identify components of the nuclear response to GH. Binding of GH to its receptor first leads to receptor dimerization and then to interaction of the receptor with the intracellular tyrosine protein kinase, Janus kinase 2 (JAK2). Subsequent activation of JAK2 generates a variety of signaling responses, including tyrosine phosphorylation of other intracellular proteins, stimulation of mitogen-activated protein (MAP) kinases and other enzymes, and activation of several transcription factors, among them signal transducers and activators of transcription (Stats) 1, 3, and 5. Our laboratory has focused on the acute biochemical and molecular biological responses to GH and has studied the early nuclear events following in vivo hormone treatment to GH-deficient rats. In this report we review recent observations showing that a single systemic injection of GH has potent effects on several nuclear signal transduction pathways in the liver, and on the transcription of a variety of hepatic genes, including insulin-like growth factor I (IGF-I), a highly-conserved, 70 amino acid secreted peptide that is a major mediator of GH-dependent somatic growth. Our results support the idea that multiple primary and secondary signaling pathways contribute to the acute actions of GH on gene expression and define a framework for identifying the biochemical mechanisms that link these early nuclear events to sustained physiological responses.

Key Words: Growth Hormone Action • Janus Kinases • Signal Transducers and Activators of Transcription • Transcription Factors • IGF-I Gene • Serine Protease Inhibitor 2.1 Gene

¹ These studies are supported by NIH Research Grants RO1-DK37449 and PO1 HD20805 (to P. R.).

² To whom correspondence should be addressed: Division of Molecular Medicine, Oregon Health Sciences University, 3181 S. W. Sam Jackson Park Road, L-455, Portland, OR 97201-3098.

³ Dept. of Internal Med. Univ. of Iowa, College of Medicine, Iowa City, IA.