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1.
J Clin Invest ; 128(1): 402-414, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29202476

RESUMO

Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program including IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis. These data indicate that IL-11-mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.


Assuntos
Transformação Celular Neoplásica , Interleucina-11/metabolismo , Neoplasias Intestinais/metabolismo , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Proteínas Quinases Ativadas por AMP , Animais , Interleucina-11/genética , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Janus Quinase 1/genética , Janus Quinase 2/genética , Camundongos , Camundongos Knockout , Mutação , Proteínas de Neoplasias/genética , Fator de Transcrição STAT3/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
2.
Pharmacogenet Genomics ; 19(12): 923-34, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19858781

RESUMO

OBJECTIVES: Characterize the expression and glucuronidation activities of the human uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT) 2A2. METHOD: UGT2A1 was cloned from nasal mucosa mRNA. Synthetic cDNA for UGT2A2 was constructed assuming exon sharing between UGT2A1 and UGT2A2 (Mackenzie et al., Pharmacogenetics and Genomics 2005, 15:677-685). Exon 1 of UGT2A2 was amplified from genomic DNA and combined with exons 2-6 of UGT2A1. UGT2A3 was cloned from liver mRNA. Quantitative reverse-transcribed-PCR (RT-PCR) was used to evaluate the expression of all the three UGTs of subfamily 2A in different tissues. Recombinant UGT2A1, UGT2A2 and UGT2A3 were expressed in baculovirus-infected insect cells and analyzed for glucuronidation activity towards different substrates. RESULTS: DNA sequencing of RT-PCR products from human nasal mucosa mRNA, confirmed exon sharing between UGT2A1 and UGT2A2. In addition, it indicated that the N-terminal signal peptide sequence of UGT2A2 is the longest among the human UGTs. Quantitative RT-PCR revealed that both UGT2A1 and UGT2A2 are mainly expressed in the nasal mucosa, and that their expression level in fetal samples was much higher than in adults. Activity assays with recombinant UGTs 2A1-2A3 showed broad substrate selectivity for UGT2A1 and UGT2A2. Although glucuronidation rates and substrate affinities were mostly higher in UGT2A1, the Km values for UDP-glucuronic acid were similar in both UGTs. In addition, there were regioselectivity differences between the two UGTs and, with a few substrates, particularly ethinylestradiol, the activity of UGT2A2 was higher. CONCLUSION: UGT2A2 is mainly expressed in the nasal mucosa and it has glucuronidation activity towards several different endobiotic and xenobiotic substrates.


Assuntos
Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Mucosa Nasal/enzimologia , Adulto , Sequência de Aminoácidos , Clonagem Molecular , Feminino , Feto/enzimologia , Regulação Enzimológica da Expressão Gênica , Glucuronosiltransferase/química , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência
3.
J Cell Sci ; 121(Pt 21): 3531-40, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18840652

RESUMO

Inactivating mutations of the tumor-suppressor kinase gene LKB1 underlie Peutz-Jeghers syndrome (PJS), which is characterized by gastrointestinal hamartomatous polyps with a prominent smooth-muscle and stromal component. Recently, it was noted that PJS-type polyps develop in mice in which Lkb1 deletion is restricted to SM22-expressing mesenchymal cells. Here, we investigated the stromal functions of Lkb1, which possibly underlie tumor suppression. Ablation of Lkb1 in primary mouse embryo fibroblasts (MEFs) leads to attenuated Smad activation and TGFbeta-dependent transcription. Also, myofibroblast differentiation of Lkb1(-/-) MEFs is defective, resulting in a markedly decreased formation of alpha-smooth muscle actin (SMA)-positive stress fibers and reduced contractility. The myofibroblast differentiation defect was not associated with altered serum response factor (SRF) activity and was rescued by exogenous TGFbeta, indicating that inactivation of Lkb1 leads to defects in myofibroblast differentiation through attenuated TGFbeta signaling. These results suggest that tumorigenesis by Lkb1-deficient SM22-positive cells involves defective myogenic differentiation.


Assuntos
Fibroblastos/metabolismo , Regulação da Expressão Gênica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proteínas Quinases Ativadas por AMP , Actinas/metabolismo , Animais , Diferenciação Celular , Deleção de Genes , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Contração Muscular , Músculos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Resposta Sérica/metabolismo , Proteínas Smad/metabolismo
4.
New Phytol ; 175(2): 230-243, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17587372

RESUMO

The SCARECROW (SCR) gene is central to root radial patterning. Its expression has not been investigated in conifers with morphologically different root types. Additional interest in SCR functions in the Pinus sylvestris root system comes from the effect of ectomycorrhiza formation on the short root apical structure. Here, the P. sylvestris SCR gene (PsySCR) was cloned and its expression investigated by northern blot and in situ hybridization of primary, lateral and short roots and mycorrhiza. Short root dichotomization was induced by auxin transport inhibitor (N-1-naphthylphthalamic acid (NPA)). PsySCR has conserved GRAS family protein motifs at the C-terminus and a variable N-terminus. PsySCR expression occurred in young root tissue and mycorrhiza. In root sections the PsySCR signal runs through the tip in initials for stele and root cap column and becomes upwards-restricted to endodermis in all root types. The PsySCR expression pattern suggests for the first time a regulatory role for SCR in maintaining the endodermal characteristics and radial patterning of roots with open meristem organization. The specific PsySCR localization is also an excellent marker for investigation of the dichotomization process in short roots.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas/genética , Micorrizas/metabolismo , Ftalimidas/farmacologia , Pinus sylvestris/genética , Raízes de Plantas/genética , Sequência de Aminoácidos , Clonagem Molecular , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Dados de Sequência Molecular , Filogenia , Pinus sylvestris/efeitos dos fármacos , Pinus sylvestris/crescimento & desenvolvimento , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo
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