This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2008-0062OCv1 40/5/620    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tomita, T. Articles by Kimura, S. Search for Related Content PubMed PubMed Citation Articles by Tomita, T. Articles by Kimura, S.

Oncostatin M Regulates Secretoglobin 3A1 and 3A2 Expression in a Bidirectional Manner

Takeshi Tomita^1,*, Atsushi Yamada^1,, Masaaki Miyakoshi¹, Taketomo Kido¹, Faruk Sheikh², Achara Srisodsai^1,3, Atsushi Miyajima⁴, Raymond P. Donnelly² and Shioko Kimura¹

¹ Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; ² Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland; ³ Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand; and ⁴ Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Shioko Kimura, Ph.D., Bldg. 37, Rm. 3118, NIH, Bethesda, MD 20892. E-mail: kimuras{at}mail.nih.gov

Secretoglobin (SCGB) 3A1 and 3A2 are members of the small molecular weight secretoglobin gene superfamily. SCGB3A1 is a tumor suppressor gene, whereas SCGB3A2 has anti-inflammatory properties. Both genes are mainly expressed in the lung and trachea in mice. Whether the expression and/or function of these two genes are related is not known. Here we show that the expression of SCGB3A1 and SCGB3A2 are bidirectionally regulated by oncostatin M (OSM) when examined in a mouse transformed Clara cell line (mtCC); SCGB3A1 is up-regulated by OSM, while SCGB3A2 is down-regulated in a time- and dose-dependent manner. OSM-activated STAT3/5, through binding to the STAT-binding element located at –201 to –209 bp in the mouse Scgb3a1 gene promoter, and the extracellular signal–regulated kinase (ERK)- and p38–mitogen-activated protein kinase (MAPK) pathways are responsible for the OSM-induced up-regulation of SCGB3A1 expression. On the other hand, the –113 to –273 bp region in the Scgb3a2 promoter appears to be responsible for the OSM induced down-regulation of the gene. No significant differences in the levels or patterns of specific DNA-binding proteins were found in the –113 to –273 bp region as determined by electrophoretic mobility shift assays. Neither the ERK- nor p38-MAPK pathways were involved in the OSM-induced reduction of Scgb3a2 promoter activity. These results suggest that OSM-induced suppression of SCGB3A2 expression is an indirect effect of OSM. Expression of the Clara cell marker, CYP2F2, was markedly decreased upon OSM treatment in parallel with the decrease of SCGB3A2 expression in mtCC cells. The differential regulation of Scgb3a1 and Scgb3a2 gene expression by OSM may explain the unique functions of these genes in the lung.

Key Words: oncostatin M • gene regulation • secretoglobin 3A1 • secretoglobin 3A2 • lung

CLINICAL RELEVANCE This research shows the physiologic importance of two lung epithelial cell–specific genes, secretoglobin 3A1 and 3A2, in normal as well as in diseased lungs, in particular where oncostatin M level is temporarily raised. The oncostatin M–induced increase/decrease of these two genes may contribute to the transition in phenotypes between proximal and distal airway epithelial cells, which are found in many chronic lung diseases.