Inhibitor of growth-4 promotes IkappaB promoter activation to suppress NF-kappaB signaling and innate immunity.
Proc Natl Acad Sci U S A
; 107(25): 11423-8, 2010 Jun 22.
Article
en En
| MEDLINE
| ID: mdl-20534538
ABSTRACT
Ing4 is a member of the inhibitor of growth (ING) family of chromatin-modifying proteins. Biochemical experiments indicate that Ing4 is a subunit of the HB01-JADE-hEAF6 histone acetyltransferase complex responsible for most nucleosomal histone H4 acetylation in eukaryotes, and transfection studies suggest that Ing4 may regulate a wide variety of cellular processes, including DNA repair, apoptosis, cell-cycle regulation, metastasis, angiogenesis, and tumor suppression. However, in vivo evidence for a physiological role for Ing4 in cell-growth regulation is lacking. We have generated Ing4-deficient mice to explore the role of Ing4 in development, tumorigenesis, and in NF-kappaB signaling. Ing4-null mice develop normally and are viable. Although mice deficient for Ing4 fail to form spontaneous tumors, they are hypersensitive to LPS treatment and display elevated cytokine responses. Macrophages isolated from Ing4-null mice have increased levels of nuclear p65/RelA protein, resulting in increased RelA binding to NF-kappaB target promoters and up-regulation of cytokine gene expression. However, increased promoter occupancy by RelA in LPS-stimulated, Ing4-null cells does not always correlate with increased NF-kappaB target-gene expression, as RelA activation of a subset of cytokine promoters also requires Ing4 for proper histone H4 acetylation. Furthermore, activation of the IkappaB alpha promoter by RelA is also Ing4-dependent, and LPS-stimulated, Ing4-null cells have reduced levels of IkappaB alpha promoter H4 acetylation and IkappaB gene expression. Thus, Ing4 negatively regulates the cytokine-mediated inflammatory response in mice by facilitating NF-kappaB activation of IkappaB promoters, thereby suppressing nuclear RelA levels and the activation of select NF-kappaB target cytokines.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
FN-kappa B
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Regiones Promotoras Genéticas
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Proteínas de Homeodominio
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Proteínas de Ciclo Celular
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Proteínas Supresoras de Tumor
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos