) Frequent homozygous and compound heterozygous deletions in FHIT at 3p14.2, the genome's most fragile site, are found in tumors and cancer cell lines. Fhit protein, the prototypical member of a new family of purine nucleotide-binding proteins, is reduced or undetectable in tumors and cancer cell lines with deletions. Expression of exogenous FHIT in lung, kidney and gastric cancer cell lines lacking endogenous FHIT suppresses tumor formation in nude mice. Thus, Fhit is a potential tumor suppressor for a large fraction of cancers of multiple sites known to involve environmental factors. This Program will investigate the involvement of FHIT in cancer with three Projects, aided by Cores A and B for Administration and Nucleic Acid analysis. Kay Huebner, Program Director and leader of Project 1, will study the function of the Fhit protein, with an emphasis on characterization of interacting proteins, to provide a basis for understanding its role in cancer. Project 2, led by Carlo Croce, will use the sequence of the FHIT gene encompassing the major fragile region to determine precise deletion endpoints in cancer-derived cell lines to clarify mechanisms of breakage at the fragile sites vis a vis environmental factors, and use this information to diagnose breakpoints in early lesions. Charles Brenner, leader of Project 3, will study the recently discovered NitFhit protein, a combined nitrilase-Fhit open reading frame, for clues to function of the NitFhit signaling pathway. He will determine NitFhit crystal structure, use Nit minus yeast cells to trap the Nit substrate and seek inhibitors of Nit function. Cores A and B will provide administration support and nucleic acid analysis which is essential in the three interactive projects. Thus, this focused, yet multidisciplinary Project sees in FHIT opportunities to grapple with some of the most pressing problems of cancer: genetic rearrangement and its relationship to susceptibility; and the molecular and cellular functions of signaling pathways that lead to tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA077738-06
Application #
7060616
Study Section
Subcommittee G - Education (NCI)
Program Officer
Couch, Jennifer A
Project Start
2000-03-01
Project End
2006-02-28
Budget Start
2005-09-28
Budget End
2006-02-28
Support Year
6
Fiscal Year
2004
Total Cost
$278,873
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Nana-Sinkam, S Patrick; Croce, Carlo M (2014) MicroRNA regulation of tumorigenesis, cancer progression and interpatient heterogeneity: towards clinical use. Genome Biol 15:445
Saldivar, Joshua C; Bene, Jessica; Hosseini, Seyed Ali et al. (2013) Characterization of the role of Fhit in suppression of DNA damage. Adv Biol Regul 53:77-85
Huebner, Kay; Saldivar, Joshua C; Sun, Jin et al. (2011) Hits, Fhits and Nits: beyond enzymatic function. Adv Enzyme Regul 51:208-17
Cirombella, Roberto; Montrone, Giuseppe; Stoppacciaro, Antonella et al. (2010) Fhit loss in lung preneoplasia: relation to DNA damage response checkpoint activation. Cancer Lett 291:230-6
Sun, Jin; Okumura, Hiroshi; Yearsley, Martha et al. (2009) Nit1 and Fhit tumor suppressor activities are additive. J Cell Biochem 107:1097-106
Pichiorri, Flavia; Okumura, Hiroshi; Nakamura, Tatsuya et al. (2009) Correlation of fragile histidine triad (Fhit) protein structural features with effector interactions and biological functions. J Biol Chem 284:1040-9
Ishii, Hideshi; Mimori, Koshi; Ishikawa, Kazuhiro et al. (2008) Fhit-deficient hematopoietic stem cells survive hydroquinone exposure carrying precancerous changes. Cancer Res 68:3662-70
Iliopoulos, Dimitrios; Fabbri, Muller; Druck, Teresa et al. (2007) Inhibition of breast cancer cell growth in vitro and in vivo: effect of restoration of Wwox expression. Clin Cancer Res 13:268-74
Semba, Shuho; Huebner, Kay (2006) Protein expression profiling identifies cyclophilin A as a molecular target in Fhit-mediated tumor suppression. Mol Cancer Res 4:529-38
Semba, Shuho; Han, Shuang-Yin; Qin, Haiyan R et al. (2006) Biological functions of mammalian Nit1, the counterpart of the invertebrate NitFhit Rosetta stone protein, a possible tumor suppressor. J Biol Chem 281:28244-53

Showing the most recent 10 out of 53 publications