Prostaglandins and hydroxy fatty acids are a family of biologically potent eicosanoids derived from arachidonic acid. These substances are rapidly catabolized and either inactivated or activated further. Prostaglandins are catabolized first by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) followed by delta13-15-ketoprostaglandin reductase (13-PGR) resulting in inactive metabolites. Cloning, characterization and structure and activity relationship at 15-PGDH have been extensively studied. However, regulation of the 15-PGDH gene expression has not been explored in any detail. We have cloned the genomic DNA of mouse 15-PGDH gene and have sequenced the 5?-flanking region. We plan to identify specific regulatory elements involved in gene expression, induced by PMA and dexamethosone and to elucidate the signal transduction pathway of androgen activated 15-PGDH expression. We have also cloned and expressed the cDNA of porcine lung 13-PGR in an active form. We propose to identify the binding domains of NADPH and 15-ketoprostaglandins of 13-PGR by photoaffinity labeling studies and to elucidate the structure and function of the enzyme by site-directed mutagenesis. Finally, we propose to purify and characterize a novel 5-hydroxyeicosanoid dehydrogenase (5-HEDH) which generates a powerful activator of leukocytes, 5-KETE, from 5-HETE. The results of this research program should provide a molecular basis of how the expression of 15-PGDH is regulated and a molecular basis of catalysis of 13-PGR. Furthermore, the program should uncover novel properties of 5-HEDH and shed some light on the role of this enzyme in the inflammatory and allergic reactions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Lin, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Pharmacy
United States
Zip Code
Tai, Hsin-Hsiung (2011) Prostaglandin catabolic enzymes as tumor suppressors. Cancer Metastasis Rev 30:409-17
Zhao, Yuhua; Weng, Chu-Chun; Tong, Min et al. (2010) Restoration of leukotriene B(4)-12-hydroxydehydrogenase/15- oxo-prostaglandin 13-reductase (LTBDH/PGR) expression inhibits lung cancer growth in vitro and in vivo. Lung Cancer 68:161-9
Wei, Jingyan; Yan, Weili; Li, Xiuling et al. (2010) Thromboxane receptor alpha mediates tumor growth and angiogenesis via induction of vascular endothelial growth factor expression in human lung cancer cells. Lung Cancer 69:26-32
Roizen, Jeffrey D; Asada, Minoru; Tong, Min et al. (2008) Preterm birth without progesterone withdrawal in 15-hydroxyprostaglandin dehydrogenase hypomorphic mice. Mol Endocrinol 22:105-12
Pham, Hung; Eibl, Guido; Vincenti, Romina et al. (2008) 15-Hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice. Mol Carcinog 47:466-77
Wei, Jingyan; Yan, Weili; Li, Xiuling et al. (2007) Activation of thromboxane receptor alpha induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells. Biochem Pharmacol 74:787-800
Tai, Hsin-Hsiung; Tong, Min; Ding, Yunfei (2007) 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer. Prostaglandins Other Lipid Mediat 83:203-8
Li, Xiuling; Wei, Jingyan; Tai, Hsin-Hsiung (2007) Activation of extracellular signal-regulated kinase by 12-hydroxyheptadecatrienoic acid in prostate cancer PC3 cells. Arch Biochem Biophys 467:20-30
Yang, Li; Amann, Joseph M; Kikuchi, Takefumi et al. (2007) Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer. Cancer Res 67:5587-93
Tong, Min; Ding, Yunfei; Tai, Hsin-Hsiung (2006) Reciprocal regulation of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase expression in A549 human lung adenocarcinoma cells. Carcinogenesis 27:2170-9

Showing the most recent 10 out of 51 publications