Mapping, genomic organization and promoter analysis of the human prostate-speci¢c membrane antigen gene Denise S. O'Keefe a , Sai L. Su 1 ; a , Dean J. Bacich a , Yutaka Horiguchi a , Ying Luo a , C. Thomas Powell a , Dorothea Zandvliet b , Pamela J. Russell c , Peter L. Molloy b , Norma J. Nowak d , Thomas B. Shows d , Cami Mullins e , Raymond A. Vonder Haar e , William R. Fair a , Warren D.W. Heston a ; * a Urologic Oncology Research Laboratory, Molecular Pharmacology and Therapeutics Division, Sloan-Kettering Institute for Cancer Research, Box 334, Memorial Sloan-Kettering Cancer Center, 1275 York Ave. New York, NY 10021, USA b CSIRO Division of Molecular Science, P.O. Box 184, North Ryde, NSW 2113, Australia c Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW 2031, Australia d Department of Human Genetics, Roswell Park Cancer Institute, New York State Department of Health, Bu¡alo, NY 14263, USA e Lark Technologies Inc., 9545 Katy Fwy, Suite 465, Houston, TX 77024, USA Received 4 May 1998; accepted 9 September 1998 Abstract Prostate-specific membrane antigen (PSMA) is a 100 kDa type II transmembrane protein with folate hydrolase and NAALAdase activity. PSMA is highly expressed in prostate cancer and the vasculature of most solid tumors, and is currently the target of a number of diagnostic and therapeutic strategies. PSMA is also expressed in the brain, and is involved in conversion of the major neurotransmitter NAAG (N-acetyl-aspartyl glutamate) to NAA and free glutamate, the levels of which are disrupted in several neurological disorders including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and schizophrenia. To facilitate analysis of the role of PSMA in carcinoma we have determined the structural organization of the gene. The gene consists of 19 exons spanning approximately 60 kb of genomic DNA. A 1244 nt portion of the 5P region of the PSMA gene was able to drive the firefly luciferase reporter gene in prostate but not breast-derived cell lines. We have mapped the gene encoding PSMA to 11p11^p12, however a gene homologous, but not identical, to PSMA exists on chromosome 11q14. Analysis of sequence differences between non-coding regions of the two genes suggests duplication and divergence occurred 22 million years ago. ß 1998 Elsevier Science B.V. All rights reserved. Keywords : Prostate-speci¢c membrane antigen; PSM; Gene duplication; Prostate cancer; Promoter 1. Introduction Prostate cancer is the leading cause of cancer and second leading cause of cancer death among Ameri- can males [1]. The major current biomarker for this disease is prostate-speci¢c antigen (PSA); however, PSA is of limited value for assessing patients with disseminated disease as it is down-regulated under conditions of low androgens, and these patients undergo androgen-ablative therapy. A potentially novel marker under development is prostate-speci¢c 0167-4781 / 98 / $ ^ see front matter ß 1998 Elsevier Science B.V. All rights reserved. PII:S0167-4781(98)00200-0 * Corresponding author. Fax: +1 (212) 717-3053; E-mail : hestonw@mskcc.org 1 Present address : Northwest Biotherapeutics, L.L.C., 120 Northgate Plaza, Seattle, WA 98125, USA. Biochimica et Biophysica Acta 1443 (1998) 113^127