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1.
Nature ; 455(7209): 72-7, 2008 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-18701888

RESUMO

Dorsal-ventral patterning in vertebrate and invertebrate embryos is mediated by a conserved system of secreted proteins that establishes a bone morphogenetic protein (BMP) gradient. Although the Drosophila embryonic Decapentaplegic (Dpp) gradient has served as a model to understand how morphogen gradients are established, no role for the extracellular matrix has been previously described. Here we show that type IV collagen extracellular matrix proteins bind Dpp and regulate its signalling in both the Drosophila embryo and ovary. We provide evidence that the interaction between Dpp and type IV collagen augments Dpp signalling in the embryo by promoting gradient formation, yet it restricts the signalling range in the ovary through sequestration of the Dpp ligand. Together, these results identify a critical function of type IV collagens in modulating Dpp in the extracellular space during Drosophila development. On the basis of our findings that human type IV collagen binds BMP4, we predict that this role of type IV collagens will be conserved.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Colágeno Tipo IV/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Transdução de Sinais , Animais , Padronização Corporal , Proteínas Morfogenéticas Ósseas/genética , Contagem de Células , Colágeno Tipo IV/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Feminino , Masculino , Ovário/citologia , Ovário/metabolismo , Ligação Proteica , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
2.
Proc Natl Acad Sci U S A ; 108(43): 17761-6, 2011 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-22006338

RESUMO

Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.


Assuntos
Carcinoma de Células Escamosas/genética , Comunicação Celular/genética , Neoplasias Pulmonares/genética , Receptor Notch1/genética , Receptor Notch2/genética , Transdução de Sinais/genética , Neoplasias Cutâneas/genética , Sequência de Bases , Códon sem Sentido/genética , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Escore Lod , Dados de Sequência Molecular , Análise de Sequência de DNA
3.
Genes Dev ; 22(18): 2578-90, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18794353

RESUMO

Morphogens are secreted signaling molecules that form concentration gradients and control cell fate in developing tissues. During development, it is essential that morphogen range is strictly regulated in order for correct cell type specification to occur. One of the best characterized morphogens is Drosophila Decapentaplegic (Dpp), a BMP signaling molecule that patterns the dorsal ectoderm of the embryo by activating the Mad and Medea (Med) transcription factors. We demonstrate that there is a spatial and temporal expansion of the expression patterns of Dpp target genes in SUMO pathway mutant embryos. We identify Med as the primary SUMOylation target in the Dpp pathway, and show that failure to SUMOylate Med leads to the increased Dpp signaling range observed in the SUMO pathway mutant embryos. Med is SUMO modified in the nucleus, and we provide evidence that SUMOylation triggers Med nuclear export. Hence, Med SUMOylation provides a mechanism by which nuclei can continue to monitor the presence of extracellular Dpp signal to activate target gene expression for an appropriate duration. Overall, our results identify an unusual strategy for regulating morphogen range that, rather than impacting on the morphogen itself, targets an intracellular transducer.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/embriologia , Transdução de Sinais , Proteína Smad4/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Humanos , Mutação , Processamento de Proteína Pós-Traducional
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