GLUCOCORTICOID ACTIONS IN PHYSIOLOGY AND PATHOLOGY
, Staff Scientitist, Unit on Pediatric Endocrinology
Nancy Z. Nader, PhD, Visiting Fellow
Sinnie Ng, BS, Predoctoral Fellow1
Mayukh Chakrabarti, Howard Hughes Medical Institute Student2
Matthew W. Bushman, BS, Student3
Glucocorticoids have a broad array of life-sustaining functions and play an important role in the therapy of several inflammatory/autoimmune/allergic and lymphoproliferative disorders. Thus, changes in tissue sensitivity to glucocorticoids may cause pathologic states and influence the course of disease. We thus continue to investigate the glucocorticoid signaling system and the clinical implications of changes in tissue sensitivity to glucocorticoids. The unit also serves as a world referral center for analyzing pathologic mutations of the glucocorticoid receptor (GR). We also conduct research to elucidate molecular mechanisms underlying the AIDS-related lipodystrophy and insulin resistance syndrome in order to increase our understanding of the physiologic/pathophysiologic interactions among the endocrine, immune, and central nervous systems.
Pathologic glucocortocoid receptor mutations causing familial/sporadic glucocorticoid resistance syndrome
This past year, we described a glucocorticoid-resistant patient from Colombia in whom we identified a novel heterozygous point mutation in the GR gene that results in the replacement of phenylalanine (F) by leucine (L) at amino acid position 737. We used cutting-edge techniques to elucidate the molecular mechanisms of target tissue glucocorticoid resistance. We also identified the pathologic mutations in another glucocorticoid-resistant kindred from Greece and initiated a study of the pathologic molecular mechanisms of its defects.
Charmandari E, Kino T. Novel causes of generalized glucocorticoid resistance. Horm Metab Res 2007;39:445-50.
Charmandari E, Kino T, Ichijo T, Jubiz W, Mejia L, Zachman K, Chrousos GP. A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. J Clin Endocrinol Metab 2007;92:3986-90.
Cyclin-dependent kinase 5, a brain-specific regulator of GR activity
We discovered that the brain-specific serine/threonine cyclin-dependent kinase 5 (CDK5) phosphorylates the GR at several serine residues located in the immunogenic domain and modulates the transcriptional activity of this receptor in a target gene–specific fashion. CDK5 is essential for brain development and has implications for the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis. Given that glucocorticoids are pivotal for brain function and that excess amounts of these hormones cause neuronal death as well as emotional and psychiatric problems, our findings suggest that aberrant activation of CDK5 may also exert pathologic actions by modulating glucocorticoid activity.
Chrousos GP, Kino T. Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 2007;10:213-9.
Kino T. Tissue glucocorticoid sensitivity: beyond stochastic regulation on the diverse actions of glucocorticoids. Horm Metab Res 2007;39:420-4.
Kino T, Ichijo T, Amin ND, Kesavapany S, Wang Y, Kim N, Rao S, Player A, Zheng YL, Garabedian MJ, Kawasaki E, Pant HC, Chrousos GP. Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: clinical implications for the nervous system response to glucocorticoids and stress. Mol Endocrinol 2007;21:1552-68.
Chemical compounds acting as inhibitors of IL-6–type cytokines
We examined the biologic activity of chemical compounds 3-O-formyl-20R, 21-epoxyresibufogenin, and 3-O-formyl-20S,21-epoxyresibufogenin, which are isolates from the Chinese toad skin extract known as the drug “Ch’an Su,” and discovered that, by attenuating the function of the common receptor subunit gp130, the compounds act as inhibitors of the IL-6–type cytokines. We also found that GW501516, a pure agonist for the peroxisome proliferator–activated receptor (PPAR) d, suppresses the activity of these cytokines by inhibiting the transcriptional activity of their downstream signal transducer and activator of transcription 3 (STAT3). The results suggest that these classes of compounds may be beneficial for the treatment of disorders in which excessive circulation/production/action of IL-6 type cytokines plays important pathologic roles.
Kino T, Boos TL, Sulima A, Siegel EM, Gold PW, Rice KC, Chrousos GP. 3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6–type cytokine actions by targeting the glycoprotein 130 subunit: potential clinical implications. J Allergy Clin Immunol 2007;120:437-44.
Kino T, Rice KC, Chrousos GP. The PPARd agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition. Eur J Clin Invest 2007;37:425-33.
Viral effects on host endocrine systems
This year, we examined the effect of the HIV-1 accessory protein Vpr on PPARg activity. Vpr is a critical regulator of lipid and glucose metabolism, and we discovered that Vpr—either administered extracellularly or expressed in the cells—suppresses PPARg agonist–induced adipocyte differentiation by suppressing the transcriptional activity of this nuclear receptor. The results suggest that plasma “circulating” Vpr, or, alternatively, Vpr produced as a consequence of direct infection of adipocytes, alters insulin sensitivity by suppressing PPARg activity, possibly contributing to the development of the lipodystrophy and insulin resistance observed in HIV-1–infected patients.
Balasubramanyam A, Mersmann H, Jahoor F, Phillips TM, Sekhar RV, Schubert U, Brar B, Iyer D, Smith EO, Takahashi H, Lu H, Anderson P, Kino T, Henklein P, Kopp JB. Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice. Am J Physiol Endocrinol Metab 2007;292:E40-8.
Kino T, Chrousos GP. Virus-mediated modulation of the host endocrine signaling systems: clinical implications. Trends Endocrinol Metab 2007;18:159-66.
Shrivastav S, Kino T, Cunningham T, Ichijo T, Schubert U, Heinklein P, Chrousos GP, Kopp JB. HIV-1 Vpr suppresses transcriptional activity of PPARg and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy. Mol Endocrinol 2007 [E-pub ahead of print].
1 Graduate Partnerships Program between the NICHD and the Chinese University of Hong Kong
2 Montgomery County Public Schools Internship
3 Left the group.
COLLABORATORS
Ashok Balasubramanyam, MD, Department of Medicine, Baylor College of Medicine, Houston, TX
George P. Chrousos, MD, Athens University Medical School, Athens, Greece
Philip W. Gold, MD, Clinical Neuroendocrinology Branch, NIMH, Bethesda, MD
Ernest S. Kawasaki, PhD, Advanced Technology Center, NCI, Gaithersburg, MD
Jeffrey B. Kopp, MD, Metabolic Diseases Branch, NIDDK, Bethesda, MD
Keiko Ozato, PhD, Program in Genomics of Differentiation, NICHD, Bethesda, MD
Harish C. Pant, PhD, Laboratory of Neurochemistry, NINDS, Bethesda, MD
George N. Pavlakis, MD, PhD, Vaccine Branch, NCI-Frederick, Frederick, MD
Kenner C. Rice, PhD, Chemical Biology Research Branch, NIDA, Bethesda, MD
For further information, contact kinot@mail.nih.gov.
