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1.
PNAS Nexus ; 2(7): pgad220, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37448957

RESUMO

Mammalian genomes encode large number of long noncoding RNAs (lncRNAs) that play key roles in various biological processes, including proliferation, differentiation, and stem cell pluripotency. Recent studies have addressed that some lncRNAs are dysregulated in human cancers and may play crucial roles in tumor development and progression. Here, we show that the lncRNA ZNNT1 is required for the proliferation and tumorigenicity of colon cancer cells with wild-type p53. ZNNT1 knockdown leads to decreased ubiquitination and stabilization of p53 protein. Moreover, we demonstrate that ZNNT1 needs to interact with SART3 to destabilize p53 and to promote the proliferation and tumorigenicity of colon cancer cells. We further show that SART3 is associated with the ubiquitin-specific peptidase USP15 and that ZNNT1 may induce p53 destabilization by inhibiting this interaction. These results suggest that ZNNT1 interferes with the SART3-USP15 complex-mediated stabilization of p53 protein and thereby plays important roles in the proliferation and tumorigenicity of colon cancer cells. Our findings suggest that ZNNT1 may be a promising molecular target for the therapy of colon cancer.

2.
Biochem Biophys Res Commun ; 519(2): 220-226, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31493864

RESUMO

While most asthma can be treated with steroids, about 10%, called severe asthma, is refractory to steroids. It has recently been shown that in a subgroup of severe asthma cases, neutrophils that infiltrate into the airways play an important role in inflammation. However, the mechanisms underlying this increased neutrophil infiltration are not well understood. Here, using a mouse model of steroid-resistant neutrophilic inflammation, we show that mice deficient for the RNA-binding protein Mex-3B have significantly less neutrophil infiltration in the airways than wild-type mice. We further demonstrate that Mex-3B post-transcriptionally upregulates CXCL2, a chemokine that induces neutrophil chemotaxis and migration. Moreover, we show that treatment with either anti-CXCL2 antibody or anti-Mex-3B antisense oligonucleotide suppresses neutrophilic allergic airway inflammation. These results suggest that Mex-3B-mediated induction of CXCL2 is crucial for steroid-resistant neutrophilic allergic airway inflammation. Our findings suggest new strategies for therapeutic intervention in steroid-resistant severe asthma.


Assuntos
Resistência a Medicamentos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Esteroides/farmacologia , Animais , Anticorpos/imunologia , Reações Antígeno-Anticorpo , Asma/tratamento farmacológico , Asma/metabolismo , Quimiocina CXCL2/imunologia , Feminino , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/metabolismo , Oligonucleotídeos/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores
3.
EMBO Rep ; 20(8): e47052, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31353791

RESUMO

Long non-coding RNAs (lncRNAs) are aberrantly expressed in many disease conditions, including cancer. Accumulating evidence indicates that some lncRNAs may play critical roles in cancer progression and metastasis. Here, we identify a set of lncRNAs that are upregulated in metastatic subpopulations isolated from colon cancer HCT116 cells in vivo and show that one of these lncRNAs, which we name CALIC, is required for the metastatic activity of colon cancer cells. We show that CALIC associates with the RNA-binding protein hnRNP-L and imparts specificity to hnRNP-L-mediated gene expression. Furthermore, we demonstrate that the CALIC/hnRNP-L complex upregulates the tyrosine kinase receptor AXL and that knockdown of CALIC or AXL using shRNA in colon cancer cells attenuates their ability to form metastases in mice. These results suggest that the CALIC/hnRNP-L complex enhances the metastatic potential of colon cancer cells.


Assuntos
Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , Receptores Proteína Tirosina Quinases/genética , Ribonucleoproteínas/genética , Animais , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Progressão da Doença , Feminino , Células HCT116 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Ribonucleoproteínas/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor Tirosina Quinase Axl
4.
Oncogene ; 37(38): 5233-5247, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29849121

RESUMO

Cells respond to a variety of cellular stresses, including DNA damage, by regulating genes whose expression modulates cell cycle arrest, DNA repair, senescence, and/or apoptosis. MicroRNAs (miRNAs) play essential roles in both normal development and disease pathogenesis by destabilizing mRNAs and inhibiting translation. In turn, miRNA biogenesis, turnover, and activity can be regulated by specific RNA-binding proteins. Here we show that Mex-3B, an hnRNP K homology (KH) domain-containing RNA-binding protein, critically modulates DNA stress-induced apoptosis by posttranscriptionally upregulating the pro-apoptotic BH3 (Bcl-2 homology region 3)-only family member Bim. Furthermore, our data indicate that binding of Mex-3B to the 3'-untranslated region (3'UTR) of Bim interferes with the interaction of an Argonaute (Ago)-miR-92a complex with a miR-92a target site present in the Bim RNA. Our results provide novel insights into the posttranscriptional mechanisms that are critical for cellular stress responses.


Assuntos
Regiões 3' não Traduzidas/genética , Apoptose/genética , Proteína 11 Semelhante a Bcl-2/genética , MicroRNAs/genética , Proteínas de Ligação a RNA/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Dano ao DNA , Regulação da Expressão Gênica , Humanos , Conformação de Ácido Nucleico , Proteína Supressora de Tumor p53/metabolismo
5.
Cell Rep ; 16(9): 2456-71, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27545879

RESUMO

Allergic airway inflammation is one of the primary features of allergic asthma. Interleukin-33 (IL-33) is recognized as a key pro-inflammatory cytokine that mediates allergic airway inflammation, and its expression is elevated in this condition, but little is known about the regulatory mechanisms underlying IL-33 induction. Here, we show that the RNA binding protein Mex-3B plays a critical role in the induction of IL-33 in the development of allergic airway inflammation. We generated Mex3b(-/-) mice and found that they develop significantly less airway inflammation than wild-type mice due to reduced induction of IL-33. Furthermore, we show that Mex-3B directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33. Moreover, we show that inhalation of an antisense oligonucleotide targeting Mex-3B suppresses allergic airway inflammation. Our data identify a signaling pathway that post-transcriptionally regulates IL-33 expression and suggest that Mex-3B could be a promising molecular target for the treatment of allergic asthma.


Assuntos
Hiper-Reatividade Brônquica/terapia , Células Epiteliais/efeitos dos fármacos , Interleucina-33/imunologia , MicroRNAs/imunologia , Oligonucleotídeos Antissenso/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Sequência de Bases , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Interleucina-33/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , MicroRNAs/genética , Conformação de Ácido Nucleico , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Ovalbumina , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Transdução de Sinais , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/patologia
6.
EMBO Rep ; 12(7): 682-9, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21617703

RESUMO

Tumour cells are known to be dependent on, or 'addicted to', not only oncogenes, but also some non-oncogenes. However, the mechanisms by which tumour cells are addicted to these genes have not been fully explained. Here, we show that overexpression of a member of the ETS family, EHF, is required for the survival of colon tumour cells that contain wild-type p53. We found that EHF directly activates the transcription of RUVBL1, an ATPase associated with chromatin-remodelling complexes. RUVBL1 blocks p53-mediated apoptosis by repressing the expression of p53 and its target genes. Moreover, we found that RUVBL1 represses p53 transcription by binding to the p53 promoter, interfering with RNF20/hBRE1-mediated histone H2B monoubiquitination and promoting PAF1-mediated histone H3K9 trimethylation. These results indicate that EHF-mediated RUVBL1 expression allows colon tumour cells to avoid p53-mediated apoptosis. Thus, EHF and RUVBL1 might be promising molecular targets for the treatment of colon tumours.


Assuntos
Apoptose , Proteínas de Transporte/metabolismo , DNA Helicases/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Apoptose/genética , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , DNA Helicases/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Histonas/metabolismo , Humanos , Metilação , Transdução de Sinais/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Ubiquitinação , Regulação para Cima
7.
Exp Ther Med ; 2(3): 457-463, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-22977525

RESUMO

PTPRD is a receptor-type tyrosine-protein phosphatase. Recent analyses of comprehensive mutations and copy numbers have revealed that PTPRD is frequently mutated and homozygously deleted in various types of cancer, including glioblastoma, melanoma, breast and colon cancer. However, the molecular functions of PTPRD in cancer progression have yet to be elucidated. Herein, PTPRD suppressed colon cancer cell migration and was required for appropriate cell-cell adhesion. In addition, PTPRD regulated cell migration in cooperation with ß-catenin/TCF signaling and its target CD44. Furthermore, expression levels of PTPRD were down-regulated in highly invasive cancers and were significantly correlated with patient survival. Our findings suggest that PTPRD is required for colon cancer invasion and progression.

8.
Development ; 137(10): 1755-64, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20430750

RESUMO

The Wingless (Wg)/Wnt signaling pathway is highly conserved throughout many multicellular organisms. It directs the development of diverse tissues and organs by regulating important processes such as proliferation, polarity and the specification of cell fates. Upon activation of the Wg/Wnt signaling pathway, Armadillo (Arm)/beta-catenin is stabilized and interacts with the TCF family of transcription factors, which in turn activate Wnt target genes. We show here that Arm interacts with a novel BED (BEAF and Dref) finger protein that we have termed Sunspot (Ssp). Ssp transactivates Drosophila E2F-1 (dE2F-1) and PCNA expression, and positively regulates the proliferation of imaginal disc cells and the endoreplication of salivary gland cells. Wg negatively regulates the function of Ssp by changing its subcellular localization in the salivary gland. In addition, Ssp was found not to be involved in the signaling pathway mediated by Arm associated with dTCF. Our findings indicate that Arm controls development in part by regulating the function of Ssp.


Assuntos
Proliferação de Células , Proteínas de Drosophila/fisiologia , Drosophila/crescimento & desenvolvimento , Fatores de Transcrição/fisiologia , Proteína Wnt1/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas do Domínio Armadillo/metabolismo , Células Cultivadas , Drosophila/genética , Drosophila/metabolismo , Drosophila/fisiologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Ligação Proteica , Glândulas Salivares/crescimento & desenvolvimento , Glândulas Salivares/metabolismo , Glândulas Salivares/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Distribuição Tecidual , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Wnt1/genética , Proteína Wnt1/metabolismo
9.
Biochem Biophys Res Commun ; 320(3): 680-4, 2004 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-15240101

RESUMO

BAMBI is a transmembrane glycoprotein related to the transforming growth factor-beta (TGF-beta)-family type I receptors and functions as a negative regulator of TGF-beta signaling during development. BAMBI is induced by BMP signaling through the evolutionary conserved BMP-responsive elements in its promoter. Furthermore, we have recently shown that Wnt/beta-catenin signaling activates transcription of BAMBI and that BAMBI expression is aberrantly elevated in most colorectal carcinomas. Here, we show that BAMBI is also directly induced by TGF-beta signaling, through the three tandem repeats of 13 bp sequences containing the SMAD-binding elements, which are distinct from the BMP-responsive element. Our findings suggest that BAMBI transcription is regulated by TGF-beta signaling through direct binding of SMAD3 and SMAD4 to the BAMBI promoter.


Assuntos
Hepatoblastoma/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Ativação Transcricional , Fator de Crescimento Transformador beta/metabolismo , Proteínas de Xenopus , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genes Reguladores/genética , Hepatoblastoma/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/genética , Fatores de Crescimento Neural , Regiões Promotoras Genéticas , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Smad , Proteína Smad3 , Proteína Smad4 , Transativadores/genética , Transativadores/metabolismo , Fator de Crescimento Transformador beta/genética
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