Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model.
Proc Natl Acad Sci U S A
; 107(8): 3534-9, 2010 Feb 23.
Article
em En
| MEDLINE
| ID: mdl-20133585
ABSTRACT
Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein-Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the gamma-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação Leucêmica da Expressão Gênica
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Transformação Celular Neoplásica
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Linfoma de Células B
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Proteínas Proto-Oncogênicas c-myc
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Peptídeos e Proteínas de Sinalização Intercelular
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Receptores Notch
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Proteínas de Membrana
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article