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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #151505
Title: SECRETORY LEUKOCYTE PROTEASE INHIBITOR MEDIATES PROLIFERATION OF HUMAN ENDOMETRIAL EPITHELIAL CELLS BY POSITIVE AND NEGATIVE REGULATION OF GROWTH-ASSOCIATED GENES

Author
item ZHANG, DAYING - UNIV/FLORIDA
item SIMMEN, ROSALIA - UAMS
item MICHEL, FRANK - UNIV/FLORIDA
item ZHAO, GE - UNIV/FLORIDA
item VALE-CRUZ, DUSTIN - UNIV/FLORIDA
item SIMMEN, FRANK - UAMS

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/7/2002
Publication Date: 5/22/2002
Citation: ZHANG, D., SIMMEN, R.C., MICHEL, F.J., ZHAO, G., VALE-CRUZ, D., SIMMEN, F.A. SECRETORY LEUKOCYTE PROTEASE INHIBITOR MEDIATES PROLIFERATION OF HUMAN ENDOMETRIAL EPITHELIAL CELLS BY POSITIVE AND NEGATIVE REGULATION OF GROWTH-ASSOCIATED GENES. JOURNAL OF BIOLOGICAL CHEMISTRY. 2002. v. 277(33). p. 29999-30009.

Interpretive Summary: This study found several new ways in which the protein known as secretory leukocyte protease inhibitor (SLPI) stimulates the growth of human uterine cells. Uterine cells were genetically engineered so that they made less or more SLPI and then their growth was studied. We found that SLPI causes increased cell growth and that this may be related to cancer of the uterus and perhaps other cancers and uterine conditions as well. This information may be useful in the future in designing strategies to counteract abnormal uterine growth that may be contributing to diseases.

Technical Abstract: Secretory leukocyte protease inhibitor (SLPI) inhibits chymotrypsin, trypsin, elastase, and cathepsin G. This protein also exhibits proliferative effects, although little is known about the molecular mechanisms underlying this activity. We have generated SLPI-ablated epithelial sublines by stably transfecting the Ishikawa human endometrial cell line with an antisense human SLPI RNA expression vector. We demonstrate a positive correlation between cellular SLPI production and proliferation. We further show that Ishikawa sublines expressing low to undetectable SLPI have correspondingly increased and decreased expression, respectively, of transforming growth factor-beta 1 and cyclin D1 genes, relative to parental cells. SLPI selectively increased cyclin D1 gene expression, with the effect occurring in part at the level of promoter activity. Cellular SLPI levels negatively influenced the anti-proliferative and pro-apoptotic insulin-like growth factor-binding protein-3 expression. We also identified lysyl oxidase, a phenotypic inhibitor of the ras oncogenic pathway and a tumor suppressor, as SLPI-repressed gene, whose expression is up-regulated by transforming growth factor-beta1. Our results suggest that SLPI acts at the node(s) of at least three major interacting growth inhibitory pathways. Because expression of SLPI is generally high in epithelial cells exhibiting abnormal proliferation such as in carcinomas, SLPI may define a novel pathway by which cellular growth is modulated.