Idioma:

Inhibition of Siah ubiquitin ligase function

MÖLLER, A ; HOUSE, C. M ; WONG, C. S. F ; SCANLON, D. B ; LIU, M. C. P ; RONAI, Z ; BOWTELL, D. D. L

Oncogene, 2009-01, Vol.28 (2), p.289-296 [Periódico revisado por pares]

Basingstoke: Nature Publishing Group

Texto completo disponível

Citações Citado por

Enviar para

Título:
Inhibition of Siah ubiquitin ligase function
Autor: MÖLLER, A ; HOUSE, C. M ; WONG, C. S. F ; SCANLON, D. B ; LIU, M. C. P ; RONAI, Z ; BOWTELL, D. D. L
Assuntos: Animals ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Breast cancer ; Breast Neoplasms - pathology ; Cell Hypoxia - genetics ; Cell Line, Tumor - metabolism ; Cell Line, Tumor - transplantation ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cellular biology ; Dioxygenases - metabolism ; DNA binding proteins ; Dosage and administration ; Drosophila ; Drosophila Proteins - genetics ; Drosophila Proteins - physiology ; Drug Delivery Systems ; Drug therapy ; Enzyme inhibitors ; Female ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Genetic aspects ; Health aspects ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases ; Mammary Neoplasms, Experimental - blood supply ; Mammary Neoplasms, Experimental - enzymology ; Metastasis ; Mice ; Mice, Inbred C57BL ; Molecular and cellular biology ; Neoplasm Proteins - physiology ; Neovascularization, Pathologic - enzymology ; Neovascularization, Pathologic - prevention & control ; Nuclear Proteins - antagonists & inhibitors ; Nuclear Proteins - genetics ; Nuclear Proteins - physiology ; Oncology ; Peptide Fragments - genetics ; Peptide Fragments - physiology ; Procollagen-Proline Dioxygenase - metabolism ; Proteasome Endopeptidase Complex - metabolism ; Protein Processing, Post-Translational ; Proteins ; Proteins - antagonists & inhibitors ; Proteins - genetics ; Proteins - physiology ; Recombinant Fusion Proteins - physiology ; Rodents ; Ubiquitin-Protein Ligases - antagonists & inhibitors ; Ubiquitin-Protein Ligases - physiology ; Ubiquitination ; Xenograft Model Antitumor Assays
É parte de: Oncogene, 2009-01, Vol.28 (2), p.289-296
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
these authors contributed equally to this work
Descrição: Tumor hypoxia induces the upregulation of hypoxia-inducible factor 1alpha (Hif-1alpha), which in turn induces the expression of genes including VEGF to recruit new blood vessel outgrowth, enabling tumor growth and metastasis. Interference with the Hif-1 pathway and neoangiogenesis is an attractive antitumor target. The hydroxylation of Hif-1alpha by prolyl-hydroxylase (PHD) proteins during normoxia serves as a recognition motif for its proteasomal degradation. However, under hypoxic conditions, hydroxylation is inhibited and furthermore, PHD proteins are themselves polyubiquitylated and degraded by Siah ubiquitin ligases. Our data demonstrate for the first time that inhibition of the interaction between Siah and PHD proteins using a fragment derived from a Drosophila protein (phyllopod) interferes with the PHD degradation. Furthermore, cells stably expressing the phyllopod fragment display reduced upregulation of Hif-1alpha protein levels and Hif-1-mediated gene expression under hypoxia. In a syngeneic mouse model of breast cancer, the phyllopod fragment reduced tumor growth and neoangiogenesis and prolonged survival of the mice. In addition, levels of Hif-1alpha and its target Glut-1 are reduced in tumors expressing the phyllopod fragment. These data show, in a proof-of-principle study, that Siah protein, the most upstream component of the hypoxia pathway yet identified, is a viable drug target for antitumor therapies.
Editor: Basingstoke: Nature Publishing Group
Idioma: Inglês

Links

Voltar para lista de resultados

Anterior Resultado 4 Avançar Ir para próxima página

Realização: Logos de Redes Sociais:

Inhibition of Siah ubiquitin ligase function

MÖLLER, A ; HOUSE, C. M ; WONG, C. S. F ; SCANLON, D. B ; LIU, M. C. P ; RONAI, Z ; BOWTELL, D. D. L

Basingstoke: Nature Publishing Group

Buscando em bases de dados remotas. Favor aguardar.