Development of spontaneous tumours and intestinal lesions in Fhit gene knockout mice

Fujishita, Teruaki; Doi, Yoshiko; Sonoshita, Masahiro; Hayashi, Hiroshi; Oshima, Masanobu; Huebner, Kay; Croce, Carlo M.; Taketo, Makoto Mark

doi:10.1038/sj.bjc.6602182

Cited by 23 publications

(14 citation statements)

References 10 publications

(9 reference statements)

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“…Overexpression of FHIT by adenoviral gene delivery in human cancer cells suppressed cell growth and induced caspase-dependent apoptosis in vitro and in vivo (16 -20). In addition, Fhit Ϫ/Ϫ and Fhit ϩ/Ϫ mice exhibited increased susceptibility to spontaneous tumors, and Fhit deficiency in mice enhanced sensitivity to the carcinogens N-nitrosomethylbenzylamine (NMBA) and dimethylnitrosamine (21)(22)(23) ionizing radiation (24,25). These biological functions of Fhit are consistent with its tumor suppressor activity.…”

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confidence: 56%

Biological Functions of Mammalian Nit1, the Counterpart of the Invertebrate NitFhit Rosetta Stone Protein, a Possible Tumor Suppressor

Semba

Han

Qin

et al. 2006

Journal of Biological Chemistry

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The "Rosetta Stone" hypothesis proposes that the existence of a fusion protein in some organisms predicts that the separate polypeptides function in the same biochemical pathway in other organisms and may physically interact. In Drosophila melanogaster and Caenorhabditis elegans, NitFhit protein is composed of two domains, a fragile histidine triad homolog and a bacterial and plant nitrilase homolog. We assessed the biological effects of mammalian Nit1 expression in comparison with Fhit and observed that: 1) Nit1 expression was observed in most normal tissues and overlapped partially with Fhit expression; 2) Nit1-deficient mouse kidney cells exhibited accelerated proliferation, resistance to DNA damage stress, and increased cyclin D1 expression; 3) cyclin D1 was up-regulated in Nit1 null mammary gland and skin; 4) Nit1 overexpression induced caspase-dependent apoptosis in vitro; and 5) Nit1 allele deficiency led to increased incidence of N-nitrosomethylbenzylamine-induced murine forestomach tumors. Thus, the biological effects of Nit1 expression are similar to Fhit effects. Adenoviruses carrying recombinant NIT1 and FHIT induced apoptosis in Fhit-and Nit1-deficient cells, respectively, suggesting that Nit1-Fhit interaction is not essential for function of either protein. The results suggest that Nit1 and Fhit share tumor suppressor signaling pathways, while localization of the NIT1 gene at a stable, rather than fragile, chromosome site explains the paucity of gene alterations and infrequentlossofexpressionoftheNIT1geneinhumanmalignancies.

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supporting

confidence: 56%

Biological Functions of Mammalian Nit1, the Counterpart of the Invertebrate NitFhit Rosetta Stone Protein, a Possible Tumor Suppressor

Semba

Han

Qin

et al. 2006

Journal of Biological Chemistry

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“…Over the last several years, evidence confirming tumor suppressor functions of Fhit has accumulated: Fhit À/À and Fhit +/À mice exhibit increased susceptibility to spontaneous tumors and deletion of a Fhit allele in mice enhances sensitivity to carcinogens, N-nitrosomethylbenzylamine and dimethylnitrosoamine (8)(9)(10)(11); deficiency of Fhit protein decreases sensitivity to DNA-damaging agents, such as mitomycin C, UVC, and ionizing radiation (12,13). Furthermore, overexpression of FHIT by adenoviral gene delivery effectively suppressed cell growth and induced caspase-dependent apoptosis in in vitro and in vivo experiments (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Protein Expression Profiling Identifies Cyclophilin A as a Molecular Target in Fhit-Mediated Tumor Suppression

Semba

Huebner²

2006

Molecular Cancer Research

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“…Fhit À/À and Fhit þ /À mice exhibit increased susceptibility to spontaneous tumors and deletion of a Fhit allele in mice enhanced sensitivity to the carcinogen, N-nitrosomethylbenzylamine (NMBA); around 80% of Fhit À/À and Fhit þ /À mice developed forestomach tumors (adenomas, papillomas and invasive carcinomas) after one dose of NMBA, compared with fewer than 8% in wild-type mice (Zanesi et al, 2001;Fujishita et al, 2004). Moreover, deficiency of Fhit protein altered sensitivity to mitomycin C, UVC and ionizing radiation in human gastric carcinoma cells, as well as mouse normal kidney cells, in clonogenic assays (Ottey et al, 2004;Hu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential

et al. 2006

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The Fhit tumor suppressor binds and hydrolyses diadenosine polyphosphates and the Fhit-substrate complex has been proposed as a proapoptotic effector, as determined by infection of susceptible cancer cells with adenoviruses carrying wild-type fragile histidine triad (FHIT) or catalytic site mutants. The highly conserved Fhit tyrosine 114 (Y114), within the unstructured loop C-terminal of the catalytic site, can be phosphorylated by Src family tyrosine kinases, although endogenous phospho-Fhit is rarely detected. To explore the importance of Y114 and identify Fhit-mediated signaling events, wild-type and Y114 mutant FHIT-expressing adenoviruses were introduced into two human lung cancer cell lines. Caspasedependent apoptosis was effectively induced only by wildtype but not Y114 mutant Fhit proteins. By expression profiling of FHIT versus mutant FHIT-infected cells, we found that survivin, an Inhibitor of Apoptosis Protein (IAP) family member, was significantly decreased by wildtype Fhit. In addition, Fhit inhibited activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway; loss of endogenous Fhit expression caused increased Akt activity in vitro and in vivo, and overexpression of constitutively active Akt inhibited Fhitinduced apoptosis. The results indicate that the Fhit Y114 residue plays a critical role in Fhit-induced apoptosis, occurring through inactivation of the PI3K-Akt-survivin signal pathway.

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Development of spontaneous tumours and intestinal lesions in Fhit gene knockout mice

Cited by 23 publications

References 10 publications

Biological Functions of Mammalian Nit1, the Counterpart of the Invertebrate NitFhit Rosetta Stone Protein, a Possible Tumor Suppressor

Biological Functions of Mammalian Nit1, the Counterpart of the Invertebrate NitFhit Rosetta Stone Protein, a Possible Tumor Suppressor

Protein Expression Profiling Identifies Cyclophilin A as a Molecular Target in Fhit-Mediated Tumor Suppression

Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential

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