The central objective of this continuation application is to determine the function of the novel cph oncogene and proto-oncogene, and the role of the activated oncogene in tumorigenesis. The cph oncogene was isolated in the PI's laboratory from chemically-initiated, neoplastic Syrian hamster embryo cells, e carcinogenesis model relevant to human neoplasia. Our previous results demonstrated that cph acts synergistically with ras in the transformation of murine fibroblasts. Results obtained during the present funding period have shown that cph is conserved from yeast to human cells and is expressed in most adult tissues, suggesting that it plays an important role in cellular regulation. In addition we have found that: i) cph is activated by point mutational deletions which result in the synthesis of truncated protein products, ii) the cph proteins have significant global homology to the yeast GDPase, and iii) when overexpressed, cph makes the cells more resistant to various forms of stress. We hypothesize that the activated cph oncogene is a disregulated, hyperactive nucleoside diphosphatase (NDPase) which provides the cells with superior stress- survival functions and proliferative advantage. This hypothesis will be tested by several approaches: 1) Analysis of structural determinants (gain and/or loss of regulatory sequences) of cph transforming activity. 2) Demonstration of the NDPase activity of the cph proteins, by complementation of GDPase-null yeast mutants and by purification, microsequencing and activity assays of native mammalian proteins. 3) Study the mechanism of cph transformation with regard to whether the NDPase activity is required and whether the cph oncoprotein is either mislocalized or interacts with abnormal cellular substrates. 4) Establish the participation of cph in the cellular stress-response pathways. These studies will expand our knowledge on the role of oncogenes in the carcinogenesis process by showing for the first time the contribution of a NDPase to malignancy. The long term goal of this proposal is to extend the knowledge gained to human cells, and to apply it to study the possible role of cph in human neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA064472-04
Application #
2639646
Study Section
Special Emphasis Panel (ZRG2-MEP (02))
Program Officer
Okano, Paul
Project Start
1995-04-01
Project End
2003-01-31
Budget Start
1998-04-15
Budget End
1999-01-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Georgetown University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
MacCarthy, Caitlin M; Notario, Vicente (2013) The ENTPD5/mt-PCPH oncoprotein is a catalytically inactive member of the ectonucleoside triphosphate diphosphohydrolase family. Int J Oncol 43:1244-52
Liu, Y; Yan, S; Wondimu, A et al. (2010) Ganglioside synthase knockout in oncogene-transformed fibroblasts depletes gangliosides and impairs tumor growth. Oncogene 29:3297-306
Villar, JoaquĆ­n; Quadri, Humair S; Song, Insun et al. (2009) PCPH/ENTPD5 expression confers to prostate cancer cells resistance against cisplatin-induced apoptosis through protein kinase Calpha-mediated Bcl-2 stabilization. Cancer Res 69:102-10
Becerra, S Patricia; Perez-Mediavilla, L Alberto; Weldon, John E et al. (2008) Pigment epithelium-derived factor binds to hyaluronan. Mapping of a hyaluronan binding site. J Biol Chem 283:33310-20
Villar, Joaquin; Arenas, Maria Isabel; MacCarthy, Caitlin M et al. (2007) PCPH/ENTPD5 expression enhances the invasiveness of human prostate cancer cells by a protein kinase C delta-dependent mechanism. Cancer Res 67:10859-68
Tirado, Oscar M; Mateo-Lozano, Silvia; Sanders, Sean et al. (2003) The PCPH oncoprotein antagonizes the proapoptotic role of the mammalian target of rapamycin in the response of normal fibroblasts to ionizing radiation. Cancer Res 63:6290-8
Solanas, Montserrat; Escrich, Eduard; Rouzaut, Ana et al. (2002) Deregulated expression of the PCPH proto-oncogene in rat mammary tumors induced with 7,12-dimethylbenz[a]anthracene. Mol Carcinog 33:219-27
Blanquez, Maria Jose; Regadera, Javier; Marino, Javier et al. (2002) Gradual deregulation and loss of PCPH expression in the progression of human laryngeal neoplasia. Mol Carcinog 35:186-95
Soldatenkov, Viatcheslav A; Trofimova, Irina N; Rouzaut, Ana et al. (2002) Differential regulation of the response to DNA damage in Ewing's sarcoma cells by ETS1 and EWS/FLI-1. Oncogene 21:2890-5
Recio, Juan A; Paez, J Guillermo; Sanders, Sean et al. (2002) Partial depletion of intracellular ATP mediates the stress-survival function of the PCPH oncoprotein. Cancer Res 62:2690-4

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