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2.
J Biol Chem ; 287(27): 23246-54, 2012 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-22593577

RESUMO

Secreted Wnt proteins constitute one of the largest families of intercellular signaling molecules in vertebrates with essential roles in embryonic development and adult tissue homeostasis. The functional redundancy of Wnt genes and the many forms of cellular responses they elicit, including some utilizing the transcriptional co-activator ß-catenin, has limited the ability of classical genetic strategies to uncover their roles in vivo. We had previously identified a chemical compound class termed Inhibitor of Wnt Production (or IWP) that targets Porcupine (Porcn), an acyltransferase catalyzing the addition of fatty acid adducts onto Wnt proteins. Here we demonstrate that diverse chemical structures are able to inhibit Porcn by targeting its putative active site. When deployed in concert with small molecules that modulate the activity of Tankyrase enzymes and glycogen synthase kinase 3 ß (GSK3ß), additional transducers of Wnt/ß-catenin signaling, the IWP compounds reveal an essential role for Wnt protein fatty acylation in eliciting ß-catenin-dependent and -independent forms of Wnt signaling during zebrafish development. This collection of small molecules facilitates rapid dissection of Wnt gene function in vivo by limiting the influence of redundant Wnt gene functions on phenotypic outcomes and enables temporal manipulation of Wnt-mediated signaling in vertebrates.


Assuntos
Inibidores Enzimáticos/farmacologia , Regeneração Tecidual Guiada/métodos , Proteínas de Membrana/antagonistas & inibidores , Alicerces Teciduais , Via de Sinalização Wnt/fisiologia , Aciltransferases , Animais , Animais Geneticamente Modificados , Antineoplásicos/farmacologia , Células COS , Membrana Celular/enzimologia , Chlorocebus aethiops , Desenho de Fármacos , Células HEK293 , Células HeLa , Humanos , Rim/citologia , Rim/embriologia , Rim/enzimologia , Proteínas de Membrana/metabolismo , Técnicas de Cultura de Órgãos , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra , beta Catenina/metabolismo
3.
Nature ; 440(7082): 346-51, 2006 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-16541075

RESUMO

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease. The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome. Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 4.5% of the human genome. Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages. The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents.


Assuntos
Cromossomos Humanos Par 12/genética , Animais , Composição de Bases , Ilhas de CpG/genética , Evolução Molecular , Etiquetas de Sequências Expressas , Genes/genética , Humanos , Desequilíbrio de Ligação/genética , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Mutagênese Insercional/genética , Pan troglodytes/genética , Análise de Sequência de DNA , Deleção de Sequência/genética , Elementos Nucleotídeos Curtos e Dispersos/genética , Sintenia/genética
4.
Nat Rev Cancer ; 18(1): 5-18, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29170536

RESUMO

Thousands of unique non-coding RNA (ncRNA) sequences exist within cells. Work from the past decade has altered our perception of ncRNAs from 'junk' transcriptional products to functional regulatory molecules that mediate cellular processes including chromatin remodelling, transcription, post-transcriptional modifications and signal transduction. The networks in which ncRNAs engage can influence numerous molecular targets to drive specific cell biological responses and fates. Consequently, ncRNAs act as key regulators of physiological programmes in developmental and disease contexts. Particularly relevant in cancer, ncRNAs have been identified as oncogenic drivers and tumour suppressors in every major cancer type. Thus, a deeper understanding of the complex networks of interactions that ncRNAs coordinate would provide a unique opportunity to design better therapeutic interventions.


Assuntos
Neoplasias/genética , RNA não Traduzido/genética , Animais , Humanos , Processamento Pós-Transcricional do RNA/genética , Transdução de Sinais/genética , Transcrição Gênica/genética
5.
Cancer Res ; 75(18): 3713-9, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26208905

RESUMO

Several experimental models faithfully recapitulate many important facets of human metastatic disease. Here, we have performed whole-exome sequencing in five widely used experimental metastasis models that were independently derived through in vivo selection from heterogeneous human cancer cell lines. In addition to providing an important characterization of these model systems, our study examines the genetic evolution of metastatic phenotypes. We found that in vivo selected highly metastatic cell populations showed little genetic divergence from the corresponding parental population. However, selection of genetic variations that preexisted in parental populations, including the well-established oncogenic mutations KRAS(G13D) and BRAF(G464V), was associated with increased metastatic capability. Conversely, expression of the wild-type BRAF allele in metastatic cells inhibited metastatic outgrowth as well as tumor initiation in mice. Our findings establish that metastatic competence can arise from heterogeneous cancer cell populations without the need for acquisition of additional mutations and that such competence can benefit from further selection of tumor-initiating mutations that seed primary tumorigenesis.


Assuntos
Exoma/genética , Metástase Neoplásica/genética , Oncogenes , Alelos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma/genética , Carcinoma/secundário , Linhagem Celular Tumoral , Hibridização Genômica Comparativa , DNA de Neoplasias/genética , Feminino , Dosagem de Genes , Xenoenxertos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Metástase Neoplásica/fisiopatologia , Transplante de Neoplasias , Especificidade de Órgãos , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Seleção Genética , Análise de Sequência de DNA , Proteínas ras/genética
6.
Sci Signal ; 4(157): ra4, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21266715

RESUMO

The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.


Assuntos
Cílios/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Transdução de Sinais/genética , Proteínas Wnt/metabolismo , Células 3T3 , Proteínas Quinases Ativadas por AMP , Aciltransferases , Animais , Western Blotting , Primers do DNA/genética , Imunofluorescência , Técnicas de Silenciamento de Genes , Genômica , Desacetilase 6 de Histona , Histona Desacetilases/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Microscopia Eletrônica de Transmissão , Proteínas do Tecido Nervoso/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Peixe-Zebra , Proteína Gli3 com Dedos de Zinco
7.
J Bacteriol ; 186(17): 5842-55, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15317790

RESUMO

Rickettsia typhi, the causative agent of murine typhus, is an obligate intracellular bacterium with a life cycle involving both vertebrate and invertebrate hosts. Here we present the complete genome sequence of R. typhi (1,111,496 bp) and compare it to the two published rickettsial genome sequences: R. prowazekii and R. conorii. We identified 877 genes in R. typhi encoding 3 rRNAs, 33 tRNAs, 3 noncoding RNAs, and 838 proteins, 3 of which are frameshifts. In addition, we discovered more than 40 pseudogenes, including the entire cytochrome c oxidase system. The three rickettsial genomes share 775 genes: 23 are found only in R. prowazekii and R. typhi, 15 are found only in R. conorii and R. typhi, and 24 are unique to R. typhi. Although most of the genes are colinear, there is a 35-kb inversion in gene order, which is close to the replication terminus, in R. typhi, compared to R. prowazekii and R. conorii. In addition, we found a 124-kb R. typhi-specific inversion, starting 19 kb from the origin of replication, compared to R. prowazekii and R. conorii. Inversions in this region are also seen in the unpublished genome sequences of R. sibirica and R. rickettsii, indicating that this region is a hot spot for rearrangements. Genome comparisons also revealed a 12-kb insertion in the R. prowazekii genome, relative to R. typhi and R. conorii, which appears to have occurred after the typhus (R. prowazekii and R. typhi) and spotted fever (R. conorii) groups diverged. The three-way comparison allowed further in silico analysis of the SpoT split genes, leading us to propose that the stringent response system is still functional in these rickettsiae.


Assuntos
Genoma Bacteriano , Rickettsia typhi/genética , Análise de Sequência de DNA , Inversão Cromossômica , DNA Bacteriano/química , DNA Bacteriano/isolamento & purificação , Complexo IV da Cadeia de Transporte de Elétrons/genética , Mudança da Fase de Leitura do Gene Ribossômico , Regulação Bacteriana da Expressão Gênica , Rearranjo Gênico , Genes Bacterianos , Genes de RNAr , Genômica , Dados de Sequência Molecular , Pseudogenes , RNA de Transferência/genética , RNA não Traduzido/genética , Rickettsia/genética , Rickettsia conorii/genética , Homologia de Sequência , Sintenia
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