Involvement of the <i>Fhit</i> gene in the ionizing radiation‐activated ATR/CHK1 pathway

Hu, Baocheng; Han, Sun‐Young; Wang, Xiang; Ottey, Michelle; Potoczek, Magdalena; Dicker, Adam P.; Huebner, Kay; Wang, Ya

doi:10.1002/jcp.20139

Cited by 49 publications

(61 citation statements)

References 32 publications

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“…Inactivation of the phosphatidylinositol 3-kinase/Akt/survivin pathway by Fhit is also implicated in Fhit-mediated apoptosis signaling (20). We assessed previously the Atr-Chk1 pathway in response to mitomycin C, UVC, and ionizing radiation in Fhit-positive and Fhit-negative cells and found that Fhitnegative cells are resistant to apoptosis induced by these genotoxic agents despite activation of the Atr-Chk1 pathway (12,13). The above proteins were not detected by this twodimensional PAGE and MALDI-TOF/MS analysis possibly because differences in protein modification (e.g., phosphorylation and dephosphorylation) or protein structure do not necessarily cause significant mobility differences in twodimensional PAGE gels.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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). Thus, Fhit plays an important role in tumorigenesis, and FHIT gene therapy is expected to be a novel clinical approach in treatment of human cancers and prevention of tumor development (Dumon et al, 2001b).…”

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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“…These findings imply that FHIT protein is required for enhanced paclitaxel-induced apoptosis. It has been reported that restoration of FHIT protein function undergoes cell cycle arrest and apoptosis in response to some stressful conditions such as those induced by external stimuli, such as serum starvation, 22 Fas treatment, 23 treatment with UVC light or mitomycin C 32 or ionizing radiation 33 better than parental cells lacking FHIT expression, suggesting that usually the FHIT proapoptotic pathway needs activation by stressful agents. Thus, it is not specific to chemotherapeutic agents that FHIT protein facilitates apoptosis in response to pro-apoptotic stimuli.…”

Section: Discussionmentioning

confidence: 99%

FHIT protein enhances paclitaxel‐induced apoptosis in lung cancer cells

Kim

Yoo

Lee

et al. 2005

Intl Journal of Cancer

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The fragile histidine triad (FHIT) gene is a frequent target of deletions in lung cancer. Previous studies have shown that FHIT gene transfer into lung cancer cells lacking FHIT expression results in induction of apoptosis. However, the effect of FHIT expression on apoptosis induced by chemotherapeutic agents and its intracellular mechanism is poorly understood. This study was undertaken to elucidate the effect of FHIT expression and the role of Bcl-2-caspase signaling in paclitaxel-induced apoptosis in lung cancer cells. NCI-H358 lung cancer cells, which lack FHIT expression, were stably transfected with plasmid vector containing FLAGtagged wildtype FHIT. We investigated effects of paclitaxel on apoptosis, activation of caspase system and expression of Bcl-2 family. We next evaluated whether these effects were reversed by blocking FHIT expression using siRNA. Paclitaxel enhanced apoptosis in FHIT-expressing cells compared to that in control vectortransfected cells, and this enhancement was suppressed by siRNA treatment. Activities of caspase-3 and caspase-7, but not of caspase-8, were higher in FHIT-expressing cells than in control vector-transfected cells, and this was reduced by siRNA treatment. When caspase activation was blocked by a pan-caspase inhibitor in FHIT-expressing cells, paclitaxel-induced apoptotic cell death was decreased similar to that in control vector-transfected cells. Bcl-2 and Bcl-xL expressions were down-regulated after paclitaxel treatment in FHIT-expressing cells, whereas Bax and Bad expressions were up-regulated. These were reversed by siRNA treatment. These results indicate that paclitaxel-induced apoptosis enhanced by FHIT expression in lung cancer cells might be associated with modulation of Bcl-2-caspase signaling. ' 2005 Wiley-Liss, Inc.Key words: fragile histidine triad (FHIT); paclitaxel; apoptosis; Bcl-2 protein; lung neoplasms Deletion of human chromosome 3p is one of the most frequently found genetic alterations in lung cancers, observed in more than 90% of small cell lung cancers and in about 80% of non-small cell lung cancers. [1][2][3][4] Further, it is known that chromosome 3p deletions occur even in an early stage of lung carcinogenesis including hyperplasia, dysplasia or carcinoma in situ. 5,6 Thus, chromosome 3p has been proposed to contain tumor suppressor genes of lung cancer, and several candidate genes have been identified. 7-10 The fragile histidine triad (FHIT) gene is located at 3p14.2 11 and its gene product, FHIT protein, is a diadenosine triphosphate (Ap3A) hydrolase belonging to the histidine triad superfamily of nucleotide-binding proteins. 12,13 Numerous studies have shown the FHIT gene is a frequent target of deletions associated with abnormal RNA and protein expression in primary tumors and cell lines of lung, esophageal, head and neck, cervical and breast cancer. [14][15][16][17] In lung cancer, FHIT inactivation has been detected very frequently. [18][19][20] For example, 80% of small cell lung cancers and 40% of non-small cell lung cancers showed abn...

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Involvement of the Fhit gene in the ionizing radiation‐activated ATR/CHK1 pathway

Cited by 49 publications

References 32 publications

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

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

FHIT protein enhances paclitaxel‐induced apoptosis in lung cancer cells

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