Anti-AKR1C4 monoclonal antibody, clone 3D22

Recently, we found a region A (a hepatocyte nuclear factor (HNF)-4-binding site from nucleoticles -701 to -684) and a region B (an HNF-1-binding site from nucleoticles -682 to -666) as cis-acting elements necessary for the transcriptional activation of the human dihydrodiol dehydrogenase (DD)4 gene in human hepatoblastoma HepG2 cells, which express DD4 mRNA [20]. Thus, to investigate the mechanism(s) responsible for the cell-type-specific expression of DD4 mRNA, we constructed a reporter plasmid, pDD4 Foot A + 13: -95/+28, in which regions A and B were linked to the human DD4 minimal promoter (-95 to 1-28) fused to the luciferase gene. The luciferase activity was detectable in HepG2 cells but not in human renal adenocarcinoma ACHN cells transfected with the pDD4 Foot A + 13: -95/+28, which do not express DD4 mRNA. A supershift assay using antibodies to HNF-4alpha, -4gamma, -1alpha, or valiant HNF (vHNF)-1 revealed that HNF-4alpha, -4gamma, and -1alpha recognized regions A and B in HepG2 cells and that only vHNF-1 bound to regions A and B in ACHN cells. Semiquantitative reverse-transcribed polymerase chain reaction showed that a large amount of vHNF-1-C, which lacked transcriptional activation domain, was expressed in ACHN cells, Transfection of ACHN cells with an expression plasmid of vHNF-1-C did not activate the pDD4 Foot A + 13: -95/+28 reporter gene. Taken together, we conclude that the cell-type-specific expression of DD4 mRNA is regulated by vHNF-1-C. (C) 2002 Elsevier Science (USA). All rights reserved.

The AKR1C aldo-keto reductases (AKR1C1-AKR1C4) are enzymes that interconvert steroidal hormones between their active and inactive forms. In this manner, they can regulate the occupancy and trans-activation of the androgen, estrogen and progesterone receptors. The AKR1C isoforms also have important roles in the production and inactivation of neurosteroids and prostaglandins, and in the metabolism of xenobiotics. They thus represent important emerging drug targets for the development of agents for the treatment of hormone-dependent forms of cancer, like breast, prostate and endometrial cancers, and other diseases, like premenstrual syndrome, endometriosis, catamenial epilepsy and depressive disorders. We present here the physiological roles of these enzymes, along with their structural properties and an overview of the recent developments regarding their inhibitors. The most important strategies of inhibitor design are described, which include the screening of banks of natural compounds (like cinnamic acids, flavonoids, jasmonates, and related compounds), the screening of and structural modifications to non-steroidal anti-inflammatory drugs, the substrate-inspired design of steroidal and nonsteroidal inhibitors, and computer-assisted structure-based inhibitor design.