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1.
ESMO Open ; 6(2): 100093, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33744811

RESUMO

BACKGROUND: Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. PATIENTS AND METHODS: Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort. RESULTS: Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. CONCLUSIONS: FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.


Assuntos
Neoplasias Colorretais , Trifluridina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Mutação , Pirrolidinas , Timina , Trifluridina/uso terapêutico
3.
Oncogene ; 33(29): 3803-11, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-24013228

RESUMO

Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy.


Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/metabolismo , Comunicação Parácrina , Trombospondina 1/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Células Endoteliais/metabolismo , Células HeLa , Humanos , Melanoma Experimental , Camundongos , Transdução de Sinais , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Carga Tumoral
4.
Br J Cancer ; 108(4): 932-40, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23385731

RESUMO

BACKGROUND: Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and a poor prognosis. There are no effective serum biomarkers for early detection of DGC. We have established an E-cadherin/p53 double conditional knockout (DCKO) mouse line that recapitulates human DGC morphologically and molecularly. In this study we tried to identify circulating microRNAs (miRNAs) as non-invasive biomarkers for DGC diagnosis using DCKO mice. METHODS: We performed miRNA microarray and quantitative reverse transcription-PCR analyses of tissue and serum samples from DCKO mice with DGC and age-matched littermate controls. RESULTS: Comparative analyses showed that mouse and human primary gastric cancers have similar miRNA expression patterns. Next, we selected some candidate miRNAs highly expressed in sera and cancer tissues of DCKO mice for further evaluation. TaqMan quantitative RT-PCR analyses indicated that four of them, miR-103, miR-107, miR-194 and miR-210, were significantly upregulated in sera of both early and advanced-stage DGC-bearing mice compared with in corresponding controls. Receiver-operating characteristic curve analyses demonstrated that these four miRNAs can discriminate DGC-positive cases from normal ones with high sensitivity and specificity. CONCLUSION: These observations suggest that this mouse model of DGC is useful for identifying serum biomarkers, and we found circulating miRNAs that can accurately detect DGC at an early stage.


Assuntos
MicroRNAs/sangue , Neoplasias Gástricas/diagnóstico , Animais , Biomarcadores , Caderinas/genética , Modelos Animais de Doenças , Diagnóstico Precoce , Estudos de Viabilidade , Genes p53 , Humanos , Camundongos , Camundongos Knockout , Técnicas de Diagnóstico Molecular , Neoplasias Gástricas/genética
6.
Br J Cancer ; 98(4): 824-31, 2008 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-18268498

RESUMO

SOX transcription factors are essential for embryonic development and play critical roles in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein is expressed in normal gastric mucosae but downregulated in some human gastric carcinomas. To clarify the roles of SOX2 in gastric carcinogenesis, we carried out functional characterisation of SOX2 in gastric epithelial cell lines. Exogenous expression of SOX2 suppressed cell proliferation in gastric epithelial cell lines. Flow cytometry analysis revealed that SOX2-overexpressing cells exhibited cell-cycle arrest and apoptosis. We found that SOX2-mediated cell-cycle arrest was associated with decreased levels of cyclin D1 and phosphorylated Rb, and an increased p27(Kip1) level. These cells exhibited further characteristics of apoptosis, such as DNA laddering and caspase-3 activation. SOX2 hypermethylation signals were observed in some cultured and primary gastric cancers with no or weak SOX2 expression. Among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation (P=0.0062). Hence, SOX2 plays important roles in growth inhibition through cell-cycle arrest and apoptosis in gastric epithelial cells, and the loss of SOX2 expression may be related to gastric carcinogenesis and poor prognosis.


Assuntos
Apoptose , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Inativação Gênica , Proteínas HMGB/metabolismo , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/metabolismo , Western Blotting , Caspases/metabolismo , Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p27 , Metilação de DNA , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Citometria de Fluxo , Proteínas HMGB/antagonistas & inibidores , Proteínas HMGB/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Proteína do Retinoblastoma , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXB1 , Neoplasias Gástricas/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Células Tumorais Cultivadas
7.
J Laryngol Otol ; 121(9): 840-4, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17166327

RESUMO

OBJECTIVE: To introduce simple underlay myringoplasty which is widely performed in Japan. PATIENTS: 391 ears with perforated eardrum underwent simple underlay myringoplasty from 2000 to 2004, and which were followed up for more than six months after surgery. METHODS: After removing the margin of the perforation by a transcanal approach under local anaesthesia, a connective tissue graft was inserted through the perforation and lifted to contact the edge. Fibrin glue was dropped on the contact area. There was no packing in the canal or in the middle-ear cavity. If the perforation remained, re-closure was attempted using the patient's frozen tissue. RESULTS: The rate of closure after the initial attempt was 304/391 (77.7 per cent), and that after re-closure for unsuccessful cases was 70/87 (80.5 per cent). The overall rate was 374/391 (95.7 per cent). There were no serious complications such as sensorineural hearing loss. CONCLUSIONS: Simple underlay myringoplasty is a simple and minimally invasive procedure employing fibrin glue and has led to a high closure rate of the eardrum.


Assuntos
Adesivo Tecidual de Fibrina/uso terapêutico , Miringoplastia/métodos , Adesivos Teciduais/uso terapêutico , Perfuração da Membrana Timpânica/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia Local , Criança , Pré-Escolar , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Resultado do Tratamento
8.
Cytokine ; 36(1-2): 69-74, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17161613

RESUMO

In order to predict the clinical benefit of interferon-beta (IFN-beta) to patients with multiple sclerosis (MS), the following markers were investigated; (1) chronological change of cytokines (IFN-gamma, TNF-alpha, IL-6, IL-10, and TGF-beta) after administration of IFN-beta, (2) untoward effects of IFN-beta such as headache and arthralgia, (3) backgrounds of the patients such as age and relapse rate, (4) efficacy of IFN-beta therapy assessed by the change of relapse rate and progression of disability. Chronological blood sampling was performed 0, 10, and 24 h after injection of IFN-beta. The increase of serum IL-6 level in response to IFN-beta administration was associated with headache, arthralgia, relapse rate before treatment, and disability score at the initiation of the therapy. Significant association of change of serum TNF-alpha with age and headache was also observed. The important finding in this study was that patients with a transient increase in IL-6 in response to IFN-beta showed a slow disease progression. This result suggests that this transient increase in the serum IL-6 predicts favorable response to IFN-beta treatment.


Assuntos
Interferon beta/uso terapêutico , Interleucina-6/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Adulto , Envelhecimento/sangue , Pessoas com Deficiência , Progressão da Doença , Feminino , Humanos , Injeções , Interferon beta/administração & dosagem , Masculino , Esclerose Múltipla/patologia , Fator de Necrose Tumoral alfa/sangue
10.
Oncogene ; 25(18): 2666-73, 2006 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-16314833

RESUMO

Recently, it was reported that exogenous bone morphogenetic protein (BMP)-2 acted as an antiproliferative agent in a variety of cell lines, including normal and cancerous gastric cell lines, indicating that BMP-2 plays an important role during cell growth. However, despite the loss of BMP-2 expression in several cancers, the underlying mechanism remains unknown. Epigenetic silencing through DNA methylation is one of the key steps during carcinogenesis. In this study, we found, through analysis by the methylation-specific polymerase chain reaction technique, CpG island methylation of the BMP-2 promoter region in gastric and colon cancer cell lines. BMP-2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. Moreover, 24 of the 56 (42.9%) gastric cancer tissues exhibited promoter methylation. Immunohistochemical staining revealed that 18 of the 24 (75%) gastric cancer tissues without methylation signals exhibited BMP-2 expression, whereas among 20 cancer tissues with strong methylation signals only four (20%) expressed BMP-2 (P = 0.0003). These findings indicate that BMP-2 methylation is strongly associated with the loss of BMP-2 protein expression in the primary gastric carcinomas. BMP-2 methylation was more often observed in diffuse type (60.7%) than in intestinal type (25%) gastric carcinomas (P = 0.007). Thus, aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be related to gastric carcinogenesis, particularly in the diffuse type.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Metilação de DNA , Epigênese Genética , Inativação Gênica , Neoplasias Gástricas/genética , Fator de Crescimento Transformador beta/genética , Idoso , Sequência de Bases , Proteína Morfogenética Óssea 2 , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Ilhas de CpG/genética , Dieta , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/patologia , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas
11.
Gut ; 53(3): 323-30, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14960508

RESUMO

BACKGROUND AND AIMS: Although it has been reported that intestinal metaplasia implicated in gastric carcinogenesis is induced by the ParaHox gene CDX2, it is unclear which genes are responsible for the formation of pseudopyloric glands and whether they play a role in gastric carcinogenesis. Pancreatic-duodenal homeobox 1 (PDX1) is also a ParaHox gene which contributes to the genesis and development of the pancreas, duodenum, and antrum. To clarify its significance for the formation of pseudopyloric glands and gastric carcinogenesis, we investigated expression of PDX1 and mucin in gastric carcinomas and surrounding mucosa. METHODS: Gastric carcinoma tissues from 95 patients were used for immunohistochemical analyses of PDX1, and mucins MUC6 and MUC5AC. RESULTS: PDX1 was found to be frequently expressed in pseudopyloric glands and intestinal metaplasia. MUC6 was more abundant than MUC5AC in pseudopyloric glands while higher levels of MUC5AC than MUC6 were evident in intestinal metaplasia. The frequency of PDX1 positive reactivity was higher in differentiated type carcinomas (39/43, 90.7%) and T1 carcinomas (42/43, 97.7%) than in undifferentiated type (33/52, 63.5%) and T2-4 (30/52, 57.7%) carcinomas. PDX1 and MUC6 double positive expression was observed in carcinomas, respectively, including the corpus, and also correlated with histological type and depth of invasion. In contrast, no link was apparent between PDX1 and MUC5AC double positive reactivity and histological type. CONCLUSION: Our study suggests that PDX1 plays an important role in the development of pseudopyloric glands, and that pseudopyloric glands may reflect a condition associated with gastric carcinogenesis.


Assuntos
Proteínas de Neoplasias/metabolismo , Lesões Pré-Cancerosas/metabolismo , Neoplasias Gástricas/metabolismo , Transativadores/metabolismo , Idoso , Western Blotting , Feminino , Mucosa Gástrica/patologia , Proteínas de Homeodomínio/metabolismo , Humanos , Técnicas Imunoenzimáticas , Modelos Logísticos , Metástase Linfática , Masculino , Metaplasia , Pessoa de Meia-Idade , Mucina-5AC , Mucina-6 , Mucinas/metabolismo , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologia
12.
Pediatr Cardiol ; 24(6): 591-4, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12947509

RESUMO

We describe a 12-year-old male with isolated noncompaction of the myocardium and associated abnormal calcification in the basal interventricular septum, and we present a review of the literature. The patient has been healthy and free of symptoms. The electrocardiogram showed abnormal Q waves in III, V1, V2, and ST elevation in V1-V3. Exercise testing demonstrated ST depression in V4 and V5. Myocardial scintigraphic examination showed a regional reduction in iodine-1,2,3-beta-methyl-iodophenylpentadecanoic acid uptake in the basal interventricular septum. Since coronary angiography demonstrated normal coronary vessels and the trabeculations were not prominent in this region, we hypothesize that coronary microcirculatory dysfunction may cause subendocardial infarction associated with calcification in the same area.


Assuntos
Calcinose/diagnóstico , Cardiomiopatias/diagnóstico , Comunicação Interventricular/diagnóstico , Criança , Diagnóstico Diferencial , Eletrocardiografia , Humanos , Masculino
14.
Hum Mol Genet ; 10(26): 3001-7, 2001 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11751682

RESUMO

Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.


Assuntos
Neoplasias da Mama/genética , Neoplasias do Colo/genética , Metilação de DNA , Síndromes Neoplásicas Hereditárias/genética , Oncogenes , Neoplasias da Mama/metabolismo , Neoplasias do Colo/metabolismo , Ilhas de CpG , Genes Supressores de Tumor , Predisposição Genética para Doença , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/fisiopatologia , Regiões Promotoras Genéticas
16.
Int J Cancer ; 94(2): 208-11, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11668499

RESUMO

To determine whether methylation of the hMLH1 promoter is related to increasing age and gastric carcinogenesis, we examined hMLH1 methylation and expression in 100 gastric cancers. hMLH1 methylation and aberrant protein expression were observed in 9 and 13 cancers, respectively. Normal and intestinal metaplastic tissues adjacent to cancers with hypermethylation did not exhibit any hMLH1 methylation, indicating that it may be specific to gastric cancers. The frequency of hMLH1 methylation significantly increased with age. These results suggest that hMLH1 methylation plays an important role in gastric carcinogenesis in old people.


Assuntos
Metilação de DNA , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , Neoplasias Gástricas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteínas Nucleares , Neoplasias Gástricas/patologia
17.
J Agric Food Chem ; 49(10): 5013-8, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11600060

RESUMO

Four isomers of the L-aspartyl-D-alanine fenchyl esters were prepared as potential peptide sweeteners. L-Aspartyl-D-alanine (+)-alpha-fenchyl ester and L-aspartyl-D-alanine (-)-beta-fenchyl ester showed sweetness with potencies 250 and 160 times higher than that of sucrose, respectively. In contrast, L-aspartyl-D-alanine (+)-beta-fenchyl ester and L-aspartyl-D-alanine (-)-alpha-fenchyl ester had the highest sweetness potencies at 5700 and 1100 times that of sucrose, respectively. In particular, L-aspartyl-D-alanine (-)-alpha-fenchyl ester had an excellent sweetness quality; but L-aspartyl-D-alanine (+)-beta-fenchyl ester did not have an excellent quality of sweetness because it displayed an aftertaste caused by the strong sweetness.


Assuntos
Dipeptídeos/síntese química , Norbornanos/síntese química , Edulcorantes/síntese química , Paladar , Dipeptídeos/química , Espectroscopia de Ressonância Magnética , Norbornanos/química , Conformação Proteica , Isoformas de Proteínas , Sacarose , Edulcorantes/química
18.
J Agric Food Chem ; 49(8): 3864-6, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11513680

RESUMO

A practical synthesis of 3-methylnonane-2,4-dione, which is an intense strawlike and fruity flavored compound, has been performed by the aldol condensation of n-hexanal and methyl ethyl ketone, followed by oxidation using sodium hypochlorite in the presence of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-N-oxide in an overall yield of 59%. The purification of 3-methylnonane-2,4-dione with high purity was performed via copper complexes.


Assuntos
Alcanos/síntese química , Aromatizantes/síntese química , Cetonas/síntese química , Óleo de Soja/química , Aldeídos/química , Butanonas/química , Cobre/química , Odorantes , Oxirredução , Hipoclorito de Sódio/química , Paladar
19.
Hear Res ; 154(1-2): 158-64, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11423226

RESUMO

In tympanoplasty, it is essential to know the condition of the stapes. However, it has been difficult to evaluate stapes mobility in routine measurement. With the eye on improving future clinical practice, in this study we developed a new, easy system of measuring stapes mobility quantitatively and, as a first step, applied it to measurement of the relationship between the load and displacement of the stapes in guinea pigs and rabbits. The stapes displacement increased linearly with an increase in load in the small displacement region, and increased nonlinearly in the large displacement region. The slope of the regression line of this stiffness curve in the small displacement region was used as an index of the stapes mobility. The values in the guinea pigs and rabbits were 16+/-7 N/m and 115+/-25 N/m, respectively. A significant difference between the two species was observed.


Assuntos
Estribo/fisiologia , Animais , Fenômenos Biomecânicos , Engenharia Biomédica/instrumentação , Peso Corporal , Cobaias , Movimento , Coelhos , Especificidade da Espécie
20.
J Neurosci Res ; 64(2): 132-43, 2001 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11288142

RESUMO

Functional analyses of neural RNA-binding proteins have focused mainly on their roles as modulators of posttranscriptional gene regulation, e.g., alternative splicing, dendritic mRNA localization, and local translation. Here we identified a mouse homologue of human IMP3, which is known to bind to and repress the translation of igf2 leader 3 mRNA. The mouse igf2 mRNA-binding protein 3 (mIMP3) is a member of the zipcode binding protein-1 (ZBP-1) family previously reported in chick fibroblast cells. mIMP3 was expressed in undifferentiated neuroepithelial cells and some postmitotic neurons at early embryonic stages (E10.5--E12.5), and its expression level decreased after the midembryonic stage (E12.5) until birth. The expression profile of mIMP3 is very similar to that of mouse igf2 leader 3 mRNA. In vitro UV cross-linking experiments showed that mIMP3 preferentially bound to igf2 leader 3 mRNA rather than igf2 leader 4 mRNA and did not bind the zipcode region of beta-actin or c-myc mRNA. Furthermore, persistent expression of mIMP3 protein in an undifferentiated P19 cell line revealed that mIMP3 inhibited neuronal differentiation morphologically and immunohistochemically. Taken together, these observations raise the possibility that mIMP3 represses neuronal differentiation through the regulation of igf2 mRNA expression.


Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Fator de Crescimento Insulin-Like II/genética , Proteínas do Tecido Nervoso/fisiologia , Proteínas de Ligação a RNA/fisiologia , Regiões 5' não Traduzidas/metabolismo , Regiões 5' não Traduzidas/efeitos da radiação , Sequência de Aminoácidos , Animais , Proteínas Aviárias , Northern Blotting , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Idade Gestacional , Humanos , Fator de Crescimento Insulin-Like II/biossíntese , Camundongos , Camundongos Endogâmicos ICR , Dados de Sequência Molecular , Família Multigênica , Proteínas de Neoplasias , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/metabolismo , Especificidade de Órgãos , RNA Mensageiro/biossíntese , RNA Mensageiro/efeitos da radiação , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/efeitos da radiação , Proteínas Recombinantes de Fusão/fisiologia , Alinhamento de Sequência , Transfecção , Células Tumorais Cultivadas , Raios Ultravioleta
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