Abstract

This proposal will investigate the expression of the LIF gene in the human fetal pituitary., in adult pituitary and pituitary adenomas and in murine AtT-20 pituitary cells. Recently published data is presented demonstrating the expression of pituitary LIF mRNA and immuno-reactive protein. RNase protection assays, immunocytochemistry and double gold immunoelectronmicroscopy will be used to study the ontogeny of human fetal pituitary cell LIF distribution and its co-localization with pituitary trophic hormones. LIF expression in normal adult pituitary and pituitary adenomas will also be studied. LIF action on the pituitary will be tested by in vitro culture of human and murine pituitary cells and measuring pituitary hormone synthesis and secretion. Recently published data demonstrated marked induction of POMC mRNA and ACTH by LIF. Responses to LIF, and the related cytokine oncostatin M were tested with other inducers of ACTH, including CRH. The specificity of endogenous LIF paracrine action was tested by using antibodies to LIF and will be further tested by utilizing antibodies to LIF receptor and gp 130 (LIF signal transducer). LIF-induced phosphorylation of p91 (Stat-1), and its role in signaling the induction of POMC will be investigated. LIF may be an intrapituitary determinant of ACTH synthesis and secretion, playing a role in differentiation of the fetal pituitary. Mice expressing either a pituitary-directed LIF transgene, or homozygous LIF-knockout mice will be studied for their pituitary responses to stress.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050238-05
Application #
6177468
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
1996-09-20
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
5
Fiscal Year
2000
Total Cost
$273,537
Indirect Cost

  Institution

Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048

  Publications

Bousquet, C; Chesnokova, V; Kariagina, A et al. (2001) cAMP neuropeptide agonists induce pituitary suppressor of cytokine signaling-3: novel negative feedback mechanism for corticotroph cytokine action. Mol Endocrinol 15:1880-90
Bousquet, C; Zatelli, M C; Melmed, S (2000) Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing. J Clin Invest 106:1417-25
Auernhammer, C J; Melmed, S (2000) Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr Rev 21:313-45
Zhang, X; Horwitz, G A; Heaney, A P et al. (1999) Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 84:761-7
Bousquet, C; Susini, C; Melmed, S (1999) Inhibitory roles for SHP-1 and SOCS-3 following pituitary proopiomelanocortin induction by leukemia inhibitory factor. J Clin Invest 104:1277-85
Auernhammer, C J; Melmed, S (1999) Interleukin-11 stimulates proopiomelanocortin gene expression and adrenocorticotropin secretion in corticotroph cells: evidence for a redundant cytokine network in the hypothalamo-pituitary-adrenal axis. Endocrinology 140:1559-66
Auernhammer, C J; Bousquet, C; Melmed, S (1999) Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter. Proc Natl Acad Sci U S A 96:6964-9
Zhang, X; Horwitz, G A; Prezant, T R et al. (1999) Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol 13:156-66
Gadelha, M R; Prezant, T R; Une, K N et al. (1999) Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene. J Clin Endocrinol Metab 84:249-56
Shimon, I; Yan, X; Magoffin, D A et al. (1998) Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion. J Clin Endocrinol Metab 83:4059-64

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