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2.
Oncogene ; 39(10): 2224-2226, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31819168

RESUMO

After publication of this Article the authors noticed errors in several figures. In Fig. 2b the Gapdh panels are incorrect. The lysates are identical to those used in Fig. 1b, therefore the Gapdh panels should be the same in both figures. In Fig. 3b the Gapdh panels for Ad-Fhit-wt and Ad-Fhit-Y114F are incorrect and have been replaced with scans from original films. In Fig. 4A the Gapdh panels are incorrect. The lysates are identical to those used in Fig. 3b, therefore the Gapdh panels should be the same in both figures. In Fig. 4Bb the Gapdh panels for Fhit siRNA were incorrect and have been replaced with scans from original films. All resupplied figures are provided below. In Fig. 5C several panels are incorrect. The Authors were unable to locate the original films for all of these panels so Fig. 5c has been deleted. The scientific conclusions of this paper have not been affected.

3.
Oncogene ; 30(1): 87-96, 2011 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-20818435

RESUMO

The oncogenic fusion protein RET/PTC3 (RP3) that is expressed in papillary thyroid carcinoma (PTC) and thyroid epithelia in Hashimoto's thyroiditis activates nuclear factor-kappa B (NF-κB) and induces pro-inflammatory gene expression; however, the mechanism of this activation is unknown. To address this, we expressed RP3 in murine embryonic fibroblasts (MEFs) lacking key classical and noncanonical NF-κB signaling components. In wild-type MEFs, RP3 upregulated CCL2, CXCL1, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor expression and activated classical but not noncanonical NF-κB. RP3-activated NF-κB in IκB kinase (IKK)ß(-/-) MEFs but not IKKα- or NF-κB essential modulator (NEMO)-deficient cells and activation was inhibited by a peptide that blocks NEMO binding to the IKKs. RP3 increased the levels of NF-κB-inducing kinase (NIK) and did not activate NF-κB in NIK-deficient MEFs. Notably, NIK stabilization was not accompanied by TRAF3 degradation demonstrating that RP3 disrupts normal basal NIK regulation. Dominant-negative NIK blocked RP3-induced NF-κB activation and an RP3 signaling mutant (RP3(Y588F)) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-κB via NIK, NEMO and IKKα. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-κB activation via stabilization of NIK.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Animais , Estabilidade Enzimática , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Transdução de Sinais , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Quinase Induzida por NF-kappaB
4.
Cytogenet Genome Res ; 118(2-4): 196-203, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18000371

RESUMO

FHIT, at a constitutively active chromosome fragile site, is often a target of chromosomal aberrations and deletion in a large fraction of human tumors. Inactivation of murine Fhit allelessignificantly increases susceptibility of mice to spontaneous and carcinogen-induced tumorigenesis. In this study, transgenic mice, carrying a human FHIT cDNA under control of the endogenous promoter, were produced to determine the effect of Fhit expression, from a nonfragile cDNA transgene outside the fragile region, on carcinogen-induced tumor susceptibility of wildtype and Fhit heterozygous mice. Mice received sufficient oral doses of N-nitrosomethybenzylamine (NMBA) to cause forestomach tumors in >80% of nontransgenic control mice. Although the level of expression of the FHIT transgene in the recombinant mouse strains was much lower than the level of endogenous Fhit expression, the tumor burden in NMBA-treated male transgenic mice was significantly reduced, while female transgenic mice were not protected. To determine if the difference in protection could be due to differences in epigenetic changes at the transgene loci in male versus female mice, we examined expression, hypermethylation and induced re-expression of FHIT transgenes in male and female mice or cells derived from them. The transgene was methylated in male and female mice and in cell lines established from male and female transgenic kidneys, the FHIT locus was both hypermethylated and deacetylated. It is likely that the FHIT transgene is more tightly silenced in female transgenic mice, leading to a lack of protection from tumor induction.


Assuntos
Hidrolases Anidrido Ácido/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Transgenes , Animais , Sequência de Bases , Western Blotting , Carcinógenos/toxicidade , Metilação de DNA , Metilases de Modificação do DNA/antagonistas & inibidores , Primers do DNA , Feminino , Inibidores de Histona Desacetilases , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/induzido quimicamente , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Oncogene ; 25(20): 2860-72, 2006 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-16407838

RESUMO

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. Caspase-dependent apoptosis was effectively induced only by wild-type 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 wild-type 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 Fhit-induced 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.


Assuntos
Hidrolases Anidrido Ácido/genética , Regulação da Expressão Gênica/fisiologia , Genes Supressores de Tumor/fisiologia , Neoplasias Pulmonares/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tirosina/metabolismo , Adenoviridae/genética , Western Blotting , Classe I de Fosfatidilinositol 3-Quinases , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose , Neoplasias Pulmonares/genética , Proteínas Associadas aos Microtúbulos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Survivina , Células Tumorais Cultivadas , Tirosina/genética
6.
Br J Cancer ; 91(9): 1669-77, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15494723

RESUMO

To identify functions of the fragile tumour suppressor gene, FHIT, matched pairs of Fhit-negative and -positive human cancer cell clones, and normal cell lines established from Fhit -/- and +/+ mice, were stressed and examined for differences in cell cycle kinetics and survival. A larger fraction of Fhit-negative human cancer cells and murine kidney cells survived treatment with mitomycin C or UVC light compared to matched Fhit-positive cells; approximately 10-fold more colonies of Fhit-deficient cells survived high UVC doses in clonigenic assays. The human cancer cells were synchronised in G1, released into S and treated with UVC or mitomycin C. At 18 h post mitomycin C treatment approximately 6-fold more Fhit-positive than -negative cells had died, and 18 h post UVC treatment 3.5-fold more Fhit-positive cells were dead. Similar results were obtained for the murine -/- cells. After low UVC doses, the rate of DNA synthesis in -/- cells decreased more rapidly and steeply than in +/+ cells, although the Atr-Chk1 pathway appeared intact in both cell types. UVC surviving Fhit -/- cells appear transformed and exhibit >5-fold increased mutation frequency. This increased mutation burden could explain the susceptibility of Fhit-deficient cells in vivo to malignant transformation.


Assuntos
Hidrolases Anidrido Ácido/fisiologia , Apoptose , Ciclo Celular , Resistencia a Medicamentos Antineoplásicos , Mitomicina/efeitos adversos , Proteínas de Neoplasias/fisiologia , Tolerância a Radiação , Neoplasias Gástricas/patologia , Hidrolases Anidrido Ácido/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas Mutadas de Ataxia Telangiectasia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos da radiação , Quinase 1 do Ponto de Checagem , Ensaio de Unidades Formadoras de Colônias , DNA/efeitos dos fármacos , DNA/efeitos da radiação , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Rim/efeitos dos fármacos , Rim/efeitos da radiação , Cinética , Camundongos , Mutação/genética , Proteínas de Neoplasias/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Raios Ultravioleta
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