Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 648
Filtrar
1.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500245

RESUMO

Vascular remodeling and angiogenesis are required to improve the perfusion of ischemic tissues. The hypoxic environment, induced by ischemia, is a potent stimulus for hypoxia inducible factor 1α (HIF-1α) upregulation and activation, which induce pro-angiogenic gene expression. We previously showed that the tyrosine phosphatase SHP-2 drives hypoxia mediated HIF-1α upregulation via inhibition of the proteasomal pathway, resulting in revascularization of wounds in vivo. However, it is still unknown if SHP-2 mediates HIF-1α upregulation by affecting 26S proteasome activity and how the proteasome is regulated upon hypoxia. Using a reporter construct containing the oxygen-dependent degradation (ODD) domain of HIF-1α and a fluorogenic proteasome substrate in combination with SHP-2 mutant constructs, we show that SHP-2 inhibits the 26S proteasome activity in endothelial cells under hypoxic conditions in vitro via Src kinase/p38 mitogen-activated protein kinase (MAPK) signalling. Moreover, the simultaneous expression of constitutively active SHP-2 (E76A) and inactive SHP-2 (CS) in separate hypoxic wounds in the mice dorsal skin fold chamber by localized magnetic nanoparticle-assisted lentiviral transduction showed specific regulation of proteasome activity in vivo. Thus, we identified a new additional mechanism of SHP-2 mediated HIF-1α upregulation and proteasome activity, being functionally important for revascularization of wounds in vivo. SHP-2 may therefore constitute a potential novel therapeutic target for the induction of angiogenesis in ischemic vascular disease.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Pele/lesões , Animais , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Nanopartículas de Magnetita , Masculino , Camundongos , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteólise , Pele/irrigação sanguínea , Remodelação Vascular
2.
Artigo em Chinês | MEDLINE | ID: mdl-31446693

RESUMO

Summary Noonan syndrome with multiple lentigines(NSML) is a disorder with syndromic hearing loss. Abnormalities of other systems in NSML have received increasing attention, but hearing loss is rarely concerned. And due to the incomplete phenotype, some patients with NSML maybe missed or maybe confused with other syndromic deafness such as Waardenburg syndrome. Our study will familiarize more otolaryngologists with Leopard syndrome. A 5-year-old boy with bilateral sensorineural hearing loss and numerous symmetrically distributed dark brown macules that had good effect of cochlear implantation was collected in this study. And his father had bilateral sensorineural hearing loss and numerous symmetrically distributed dark brown macules. Waardenburg syndrome was initially diagnosed by clinical phenotype and its molecular etiology was confirmed by gene diagnosis. Waardenburg syndrome-related deafness genes and 131 known deafness genes were not identified by second-generation sequencing. Whole-exon sequencing was performed for 4 individuals in the family and the results were confirmed by Sanger sequencing. This study confirmed the diagnosis by identifying a disease-causing mutation in the PTPN11 gene, which was a heterozygous missense mutation at p. Tyr279Cys(c. 836A>G). The mutation co-segregated with hearing loss in the family. Our results demonstrated that hearing loss in this family was caused by heterozygous mutations in PTPN11. These cases will familiarize more otolaryngologists with NSML, and they emphasize the importance of considering NSML as a possible cause of hearing problems.


Assuntos
Surdez/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Pré-Escolar , Heterozigoto , Humanos , Masculino , Mutação , Síndrome de Waardenburg
3.
Artigo em Chinês | MEDLINE | ID: mdl-31446698

RESUMO

Summary PTPN11 gene encodes tyrosine phosphatase SHP-2 which locates on chromosome 12(12q24.1), expresses in most embryonic and adult tissues, and plays pivotal roles in cell proliferation, differentiation, survival and cell death. SHP-2 apparently participates in signaling events downstream of RAS-MAPK and JAK/STAT. Diseases related to PTPN11 gene mutations include the Noonan syndrome(NS) and the NS with Multiple Lentigines(NSML). Both NS and NSML contain the phenotypes of deafness, craniofacial anomalies, short stature, congenital heart defects, skin disorders, ophthalmologic abnormalities and cancer predisposition.


Assuntos
Surdez/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Humanos , Mutação , Síndrome de Noonan/classificação , Fenótipo , Transdução de Sinais
4.
Genes (Basel) ; 10(7)2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277422

RESUMO

While the genetic contributions to the predisposition of Bernese mountain dogs (BMDs) to histiocytic sarcoma (HS) remains unclear, some insights into key genetic drivers have been gained. Our group recently reported a mutation in the PTPN11 gene (E76K). We have now identified a second missense mutation in PTPN11 (G503V), and a mutation in KRAS (Q61H) present in HS cell lines. These mutations are associated with malignancies in humans, and known to be gain-of-function mutations that result in activation of the mitogen-activated protein kinase (MAPK) pathway. The goal of the present study was to evaluate the prevalence of these mutations in a large sample of HS cases from BMDs and golden retrievers, and in lymphoma cases, from a cohort of BMDs. Mutations in PTPN11 were present in HS in 41/96 (43%) BMDs, and in 3/13 (23%) golden retrievers. PTPN11 mutations E76K and G503V did not coexist in the same neoplasm. The KRAS mutation was much less frequent, with a prevalence of 3.1% (3/96). We did not identify either PTPN11 nor KRAS mutations in any of the lymphoma samples. These results point out the potential relevance of PTPN11 and KRAS mutations as activators of the oncogenic MAPK pathway for canine HS, particularly in BMDs.


Assuntos
Doenças do Cão/genética , Cães/genética , Sarcoma Histiocítico/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Feminino , Mutação com Ganho de Função , Sistema de Sinalização das MAP Quinases , Masculino
5.
Neurology ; 93(3): e237-e251, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31197031

RESUMO

OBJECTIVE: Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH). METHODS: Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples. RESULTS: We identified a germline variant of KIAA0556, which encodes a ciliary protein, and 2 somatic variants of PTPN11, which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included DYNC2H1, which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of DYNC2H1 arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of DYNC2H1). Furthermore, a combination of a germline and a somatic DYNC2H1 variant was detected in another patient. CONCLUSIONS: Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.


Assuntos
Dineínas do Citoplasma/genética , Hamartoma/genética , Doenças Hipotalâmicas/genética , Proteínas Associadas aos Microtúbulos/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cílios , Epilepsias Parciais/fisiopatologia , Epilepsia Parcial Complexa/fisiopatologia , Feminino , Mutação em Linhagem Germinativa , Hamartoma/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Hipotalâmicas/fisiopatologia , Lactente , Recém-Nascido , Sistema de Sinalização das MAP Quinases , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Transdução de Sinais , Sequenciamento Completo do Exoma , Adulto Jovem
6.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232041

RESUMO

BACKGROUND: Most cases of acute myeloid leukemia (AML) have multiple driver mutations. METHODS: We report a rare AML case with seven mutations and an aggressive clinical course. RESULTS: A 69-year-old woman presented with nausea and vomiting. A bone marrow smear showed increased mye-loblasts, promonocytes, and monocytes. Immunophenotyping identified myeloid and monocytic markers. Fusion transcripts were not detected. Massive parallel sequencing showed seven variants in DNMT3A, FLT3, KRAS, NPM1, PTPN11, and TET2. Five days after beginning chemotherapy, the patient expired. CONCLUSIONS: These findings may provide insight into the link between multiple mutations and poor prognosis.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide/genética , Mutação , Doença Aguda , Idoso , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Evolução Fatal , Feminino , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/tratamento farmacológico , Proteínas Nucleares/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Tirosina Quinase 3 Semelhante a fms/genética
7.
Mol Cells ; 42(6): 441-447, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31250618

RESUMO

RAS gene mutations are frequently found in one third of human cancers. Affecting approximately 1 in 1,000 newborns, germline and somatic gain-of-function mutations in the components of RAS/mitogen-activated protein kinase (RAS/MAPK) pathway has been shown to cause developmental disorders, known as RASopathies. Since RAS-MAPK pathway plays essential roles in proliferation, differentiation and migration involving developmental processes, individuals with RASopathies show abnormalities in various organ systems including central nervous system. The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations. Some of the defects stemmed from dysregulation of molecular and cellular processes affecting early neurodevelopmental processes. In this review, we will discuss the implications of RAS-MAPK pathway components in neurodevelopmental processes and pathogenesis of RASopathies.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Proteínas ras/genética , Síndrome de Costello/genética , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Neoplasias/metabolismo , Neurofibromatose 1/genética , Nevo Sebáceo de Jadassohn/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteína SOS1/genética , Transdução de Sinais/genética
8.
Blood ; 134(11): 900-905, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31221673
9.
Horm Res Paediatr ; 91(4): 252-261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31132774

RESUMO

OBJECTIVES: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). MATERIALS AND METHODS: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). RESULTS: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were -3.1 ± 0.7 and -0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11- patients. GV SDS increased from -1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from -1.9 ± 2.6 to -0.1 ± 2.6 in PTPN11- patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11- (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were -2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. CONCLUSIONS: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11- patients showed a poor response to rhGH. However, this PTPN11- group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.


Assuntos
Estatura/efeitos dos fármacos , Hormônio do Crescimento Humano/administração & dosagem , Mutação , Síndrome de Noonan , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adulto , Estatura/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/genética , Síndrome de Noonan/fisiopatologia , Estudos Retrospectivos
10.
EBioMedicine ; 42: 120-132, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30905847

RESUMO

BACKGROUND: Sepsis, the most severe form of infection, involves endothelial dysfunction which contributes to organ failure. To improve therapeutic prospects, elucidation of molecular mechanisms underlying endothelial vascular failure is of essence. METHODS: Polymicrobial contamination induced sepsis mouse model and primary endothelial cells incubated with sepsis serum were used to study SHP-2 in sepsis-induced endothelial inflammation. SHP-2 activity was assessed by dephosphorylation of pNPP, ROS production was measured by DCF oxidation and protein interactions were assessed by proximity ligation assay. Vascular inflammation was studied in the mouse cremaster model and in an in vitro flow assay. FINDINGS: We identified ROS-dependent inactivation of the tyrosine phosphatase SHP-2 to be decisive for endothelial activation in sepsis. Using in vivo and in vitro sepsis models, we observed a significant reduction of endothelial SHP-2 activity, accompanied by enhanced adhesion molecule expression. The impaired SHP-2 activity was restored by ROS inhibitors and an IL-1 receptor antagonist. SHP-2 activity inversely correlated with the adhesive phenotype of endothelial cells exposed to IL-1ß as well as sepsis serum via p38 MAPK and NF-κB. In vivo, SHP-2 inhibition accelerated IL-1ß-induced leukocyte adhesion, extravasation and vascular permeability. Mechanistically, SHP-2 directly interacts with the IL-1R1 adaptor protein MyD88 via its tyrosine 257, resulting in reduced binding of p85/PI3-K to MyD88. INTERPRETATION: Our data show that SHP-2 inactivation by ROS in sepsis releases a protective break, resulting in endothelial activation. FUND: German Research Foundation, LMU Mentoring excellence and FöFoLe Programme, Verein zur Förderung von Wissenschaft und Forschung, German Ministry of Education and Research.


Assuntos
Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Sepse/metabolismo , Sepse/fisiopatologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Ativação Enzimática , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Fosforilação , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Espécies Reativas de Oxigênio/metabolismo , Sepse/etiologia
11.
Orphanet J Rare Dis ; 14(1): 29, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732632

RESUMO

BACKGROUND: The RASopathies are a class of developmental disorders caused by germline mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway. Hypertrophic cardiomyopathy (HCM) has been frequently described in children with RASopathy, but only a minority of patients have received formal genotyping. The purpose of this study was to evaluate the genetic basis and clinical outcome of pediatric patients with RASopathy-associated HCM. METHODS: We retrospectively reviewed the mutation spectrum and clinical outcome of all the patients with RASopathy derived from 168 pediatric HCM cases referred to our institution between January 2012 and July 2018. RESULTS: A heterozygous missense mutation in one of known RASopathy genes was identified in 46 unrelated children with HCM. Mutations in the PTPN11 gene were the most prevalent (19/46); this was followed by mutations in RAF1 (11/46), KRAS (5/46), RIT1 (4/46), BRAF (3/46), SOS1 (2/46), HRAS (1/46), and SHOC2 (1/46). Moreover, two compound heterozygous missense mutations in the LZTR1 gene were identified in one patient with the Noonan syndrome phenotype and HCM. The median age at the diagnosis of HCM was 3.0 months (range 0 months to 8.1 years). Twenty-one of the patients had significant left ventricular outflow tract obstruction and 32 had concomitant congenital heart disease. Three patients with a mutation in exon 13 of the PTPN11 gene died of cardiac failure at the ages of 3.0, 3.5, and 6.0 months. The remaining 44 patients were alive after an average follow-up time of 3.9 years (0.5 to 17.1 years, median 2.9 years) from the initial diagnosis of HCM, including 5 patients with spontaneous regression of their cardiac hypertrophy. CONCLUSIONS: RASopathy-associated HCM is a heterogeneous genetic condition characterized by early-onset cardiac hypertrophy and a high prevalence of co-existing congenital heart disease, which is most frequently related to specific mutations in the PTPN11 gene. Rapidly progressive HCM, resulting in an early death, is uncommon in RASopathy patients except those with specific mutations in exon 13 of the PTPN11 gene.


Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Proteínas Quinases Ativadas por Mitógeno/genética , Criança , Pré-Escolar , Estudos de Coortes , Éxons/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação de Sentido Incorreto/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Estudos Retrospectivos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
12.
Nat Med ; 25(3): 462-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30742119

RESUMO

Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Feminino , Perfilação da Expressão Gênica , Genômica , Glioblastoma/genética , Glioblastoma/imunologia , Humanos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/imunologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Linfócitos T/imunologia , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adulto Jovem
13.
Mol Genet Genomic Med ; 7(4): e00581, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30784236

RESUMO

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant disorder that belongs to a group of developmental disorders called RASopathies with overlapping features and multiple causative genes. The aim of the study was to identify mutations underlying this disorder in patients from Southeast Asia and characterize their clinical presentations. METHODS: Patients were identified from the hospital's Genetics clinics after assessment by attending clinical geneticists. A targeted gene panel was used for next-generation sequencing on genomic DNA extracted from the blood samples of 17 patients. RESULTS: Heterozygous missense variants were identified in 13 patients: eight were in PTPN11, three in SOS1, and one each in RIT1 and KRAS. All are known variants that have been reported in patients with NS. Of the 13 patients with identified variants, 10 had short stature, the most common feature for NS. Four of the eight patients with PTPN11 variants had atrial septal defect. Only two had pulmonary stenosis which is reported to be common for PTPN11 mutation carriers. Another two had hypertrophic cardiomyopathy, a feature which is negatively associated with PTPN11 mutations. CONCLUSIONS: Our study provides the mutation and phenotypic spectrum of NS from a new population group. The molecular testing yield of 76% is similar to other studies and shows that the targeted panel approach is useful for identifying genetic mutations in NS which has multiple causative genes. The molecular basis for the phenotypes of the remaining patients remains unknown and would need to be uncovered via sequencing of additional genes or other investigative methods.


Assuntos
Taxa de Mutação , Síndrome de Noonan/genética , Fenótipo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Singapura , Proteínas ras/genética
14.
J Exp Med ; 216(2): 337-349, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610104

RESUMO

Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10-based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10-STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-α is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.


Assuntos
Colo/imunologia , Interleucina-10/imunologia , Macrófagos/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/imunologia , Transdução de Sinais/imunologia , Animais , Colo/patologia , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
15.
Stem Cell Res ; 34: 101374, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30640061

RESUMO

Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD Syndrome, is a rare autosomal dominant disorder. Approximately 90% of NSML cases are caused by missense mutations in the PTPN11 gene which encodes the protein tyrosine phosphatase SHP2. A human induced pluripotent stem cell (iPSC) line was generated using peripheral blood mononuclear cells (PBMCs) from a patient with NSML that carries a gene mutation of p.Q510P on the PTPN11 gene using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for drug development to treat NSML.


Assuntos
Técnicas de Cultura de Células/métodos , Células-Tronco Pluripotentes Induzidas/patologia , Síndrome LEOPARD/genética , Síndrome LEOPARD/patologia , Mutação/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adolescente , Sequência de Bases , Linhagem Celular , Feminino , Humanos
16.
Pediatr Dev Pathol ; 22(4): 386-390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30665336

RESUMO

Noonan syndrome is a genetic condition with a heterogeneous phenotype and multisystem involvement. The pathogenesis of this disorder has been attributed to the mutations in the RAS/MAPK signaling pathway involved in cell proliferation and differentiation. The most common clinical presentations are related to cardiovascular abnormalities with congestive heart failure as the most common mechanism of death. We present the autopsy findings from a Noonan syndrome patient who died as a result of an unusual form of right ventricular obstruction associated with a rare PTPN11 variant previously reported without details of the cardiac findings. Discussion follows that includes overview of the incidence, genetic causes, types of right-sided obstructive lesions, PTPN11 genotype-cardiac phenotype correlations, and other potential mechanisms that may contribute to disease heterogeneity.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Síndrome de Noonan/diagnóstico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Transdução de Sinais/genética , Autopsia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Humanos , Recém-Nascido , Masculino , Mutação , Mutação de Sentido Incorreto , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Fenótipo
17.
Pediatr Blood Cancer ; 66(5): e27625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30693642

RESUMO

Noonan syndrome (NS) is an autosomal dominant disorder commonly caused by PTPN11 germline mutations. Patients are characterized by short stature, congenital heart defects, facial dysmorphism, and increased risk of malignancies including brain tumors. Commonly associated brain tumors are dysembryoplastic neuroepithelial tumor and low-grade glioma. We report two cases of anaplastic astrocytoma with PTPN11-related NS. We conducted a systematic search of medical databases looking for other reported cases of high-grade glioma associated with NS and identified 24 cases of brain tumors, all of which were low-grade glial or glioneuronal tumors except for one case of medulloblastoma.


Assuntos
Neoplasias Encefálicas/patologia , Mutação em Linhagem Germinativa , Glioma/patologia , Síndrome de Noonan/complicações , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adolescente , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Criança , Feminino , Glioma/etiologia , Glioma/terapia , Humanos , Masculino , Gradação de Tumores
18.
Blood ; 133(10): 1060-1070, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30670449

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood. It is classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization and shares some features with chronic myelomonocytic leukemia in adults. JMML pathobiology is characterized by constitutive activation of the Ras signal transduction pathway. About 90% of patients harbor molecular alterations in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, or CBL), which define genetically and clinically distinct subtypes. Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children, whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells. The clinical course of the disease varies widely and can in part be predicted by age, level of hemoglobin F, and platelet count. The majority of children require allogeneic hematopoietic stem cell transplantation for long-term leukemia-free survival, but the disease will eventually resolve spontaneously in ∼15% of patients, rendering the prospective identification of these cases a clinical necessity. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive for outcome. Understanding the genomic and epigenomic basis of JMML will not only greatly improve precise decision making but also be fundamental for drug development and future collaborative trials.


Assuntos
GTP Fosfo-Hidrolases/genética , Leucemia Mielomonocítica Juvenil/genética , Proteínas de Membrana/genética , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Alelos , Criança , Pré-Escolar , Anormalidades Congênitas/genética , Metilação de DNA , Intervalo Livre de Doença , Epigenômica , Transplante de Células-Tronco Hematopoéticas , Heterozigoto , Humanos , Leucemia Mielomonocítica Juvenil/complicações , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Transdução de Sinais , Síndrome , Transplante Homólogo , Resultado do Tratamento
19.
Med. clín (Ed. impr.) ; 152(2): 62-64, ene. 2019.
Artigo em Inglês | IBECS | ID: ibc-181822

RESUMO

Introduction and objective: Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. Patients and methods: We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. Results: Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. Discussion: These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations


Introducción y objetivo: El síndrome de Noonan (SN) es un trastorno genético caracterizado por una amplia gama de signos distintivos y problemas de salud. Está causado en el 50% de los casos por mutaciones missense en el gen PTPN11. Se ha postulado que es posible predecir el curso de la enfermedad en función del impacto de las mutaciones en la proteína. Pacientes y métodos: Presentamos 2 casos de fenotipo severo de SN con hydrops fetalis. En ambos casos se realizó la secuenciación del gen PTPN11 en células germinales. Resultados: Se identificaron 2 mutaciones diferentes en dicho gen (p.Gly503Arg y p.Met504Val). Discusión: Estas mutaciones ya han sido identificadas previamente, y cuando se presentan en línea germinal, los pacientes pueden presentar SN clásico, SN con alteraciones malignas o recientemente, p.Gly503Arg se ha observado en un paciente con SN e hydrops fetalis, como los 2 casos que presentamos. Por tanto, estas observaciones muestran, que en pacientes con SN y mutaciones en el gen PTPN11, no es siempre posible determinar la relación genotipo-fenotipo en función del impacto de la mutación en la proteína


Assuntos
Humanos , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fenótipo , Mutação/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
20.
Oncogene ; 38(13): 2275-2290, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30467378

RESUMO

Overexpression of the human epidermal growth factor receptor 2 (HER2) is the cause of HER2-positive breast cancer (BC). Although HER2-inactivating therapies have benefited BC patients, development of resistance and disease recurrence have been the major clinical problems, pointing to a need for alternative therapeutic strategies. For that to happen, proteins that play critical roles in the biology of HER2-induced tumorigenesis have to be identified and characterized. Here, we show that the Src homology phosphotyrosyl phosphatase 2 (Shp2) encoded by the Ptpn11 gene is a requisite for ErbB2-induced tumorigenesis. We report that conditional knockout of Shp2 alleles in the ErbB2 BC model mice abrogates mammary tumorigenesis by blocking the expression of the ErbB2 transgene. We also show that inhibition of SHP2 encoded by the PTPN11 gene in the HER2-amplified BC cells induces a normal-like cellular phenotype and suppresses tumorigenesis and metastasis by blocking HER2 overexpression. These findings demonstrate that ErbB2-induced tumors in mice or xenograft tumors induced by transplantation of HER2-amplified BC cells are vulnerable to SHP2 inhibition since it abrogates the expression of the very oncogene that causes of the disease. This report paves the way for developing SHP2-targeting therapies for BC treatment in the future.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama , Carcinogênese , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor ErbB-2/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Amplificação de Genes/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Oncogenes/efeitos dos fármacos , Oncogenes/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA