The long term goal of this research is to elucidate the role and function of the tumor-associated alkaline phosphatases (APs) during normal development and the significance of their re-expression in cancer cells. The present proposal focuses sharply on the human germ cell alkaline phosphatase (GCAP) isozyme gene as a paradigm for the other Aps isozymes. The related placental (PLAP) isozyme will continuously be compared to GCAP to identify those properties unique to GCAP or shared by other APs. GCAP is expressed during germ cell development and is often reexpressed in testicular and ovarian cancer. The proposed experiments will answer the questions: What DNA sequences and factors are responsible for the developmental regulation and tissue-specific expression of GCAP? What are the in vivo substrates and/or ligands of GCAP? Answer to these questions will provide valuable clues to understanding the reexpression of GCAP in cancer. We will look for evidence of defective GCAP and/or PLAP alleles as possible causes of certain cases of spontaneous abortion. Knowledge of the in vivo function of GCAP will make the interpretation of these results more precise. Finally, the proposed experiments will focus on taking advantage of the overexpression of GCAP in cancer cells for improving the diagnosis and treatment of tumors. Consequently, the Specific Aims are: (I) To characterize in detail the regulatory sequences that account for the expression of the 1.7 kb GCAP promoter in tumor cell lines, early embryos and in germ cells. (II) To identify the in vivo substrates of GCAP and to investigate if there is functional cooperativity between AP subunits in tumoral GCAP/PLAP heterodimers. (III) To examine DNA samples from cases of spontaneous abortions for the presence of deficient GCAP and/or PLAP alleles or haplotypes. (IV) To evaluate an immunotherapy approach for the treatment of GCAP and PLAP-containing tumors based on bifunctional antibodies directed to PLAP/GCAP and CD-3 T cell marker. (V) A) to correlate the expression of GCAP and PLAP in ovarian cancer with its histologic type, ploidy and metastatic potential, B) to develop a diagnostic procedure using monoclonal antibodies to GCAP to isolate and identify carcinoma-in-situ in seminal fluid to identify individuals at high risk of developing testicular cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Medical Biochemistry Study Section (MEDB)
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Freeman, Colette S
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Sanford-Burnham Medical Research Institute
La Jolla
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Wada, Akihiro; Wang, Ai-Ping; Isomoto, Hajime et al. (2005) Placental and intestinal alkaline phosphatases are receptors for Aeromonas sobria hemolysin. Int J Med Microbiol 294:427-35
Anderson, H Clarke; Sipe, Joseph B; Hessle, Lovisa et al. (2004) Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase-deficient mice. Am J Pathol 164:841-7
Johnson, Kristen; Goding, James; Van Etten, Deborah et al. (2003) Linked deficiencies in extracellular PP(i) and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression. J Bone Miner Res 18:994-1004
Coburn, Stephen P; Slominski, Andrzej; Mahuren, J Dennis et al. (2003) Cutaneous metabolism of vitamin B-6. J Invest Dermatol 120:292-300
Narisawa, Sonoko; Huang, Lei; Iwasaki, Arata et al. (2003) Accelerated fat absorption in intestinal alkaline phosphatase knockout mice. Mol Cell Biol 23:7525-30
Weissig, Helge; Narisawa, Sonoko; Sikstrom, Carin et al. (2003) Three novel spermatogenesis-specific zinc finger genes. FEBS Lett 547:61-8
Akama, Tomoya O; Nakagawa, Hiroaki; Sugihara, Kazuhiro et al. (2002) Germ cell survival through carbohydrate-mediated interaction with Sertoli cells. Science 295:124-7
Zafarana, Gaetano; Gillis, Ad J M; van Gurp, Ruud J H L M et al. (2002) Coamplification of DAD-R, SOX5, and EKI1 in human testicular seminomas, with specific overexpression of DAD-R, correlates with reduced levels of apoptosis and earlier clinical manifestation. Cancer Res 62:1822-31
Magnusson, P; Arlestig, L; Paus, E et al. (2002) Monoclonal antibodies against tissue-nonspecific alkaline phosphatase. Report of the ISOBM TD9 workshop. Tumour Biol 23:228-48
Narisawa, Sonoko; Hecht, Norman B; Goldberg, Erwin et al. (2002) Testis-specific cytochrome c-null mice produce functional sperm but undergo early testicular atrophy. Mol Cell Biol 22:5554-62

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