Interleukin-1 Induces Increased Transcriptional Activation of the Transforming Growth Factor- -activating Integrin Subunit 8 through Altering Chromatin Architecture

Department Pathology, School of Medicine, University of California, San Francisco, California 94110, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2011; 286(42):36864-74. DOI: 10.1074/jbc.M111.276790
Source: PubMed


The integrin αvβ8 is a cell surface receptor for the latent domain (LAP) of the multifunctional cytokine TGF-β. Through its association with LAP, TGF-β is maintained in a latent form that must be activated to function. Binding to the integrin αvβ8 with subsequent metalloproteolytic cleavage of LAP represents a major mechanism of TGF-β activation in vivo. Altered expression of the integrin β8 subunit (ITGB8) is found in human chronic obstructive pulmonary disease, cancers, and brain vascular malformations. We have previously shown that the proinflammatory cytokine interleukin-1β (IL-1β) increases ITGB8 expression on lung fibroblasts, which increases αvβ8-mediated TGF-β activation in fibrosis and pathologic inflammation. Here we report the mechanism of increased ITGB8 expression by IL-1β. Our data support a model where the chromatin architecture of the ITGB8 core promoter is altered by nucleosomal repositioning that enhances the interaction of an AP1 complex (containing c-Jun and ATF2). This repositioning is caused by the dissociation of HDAC2 with the ITGB8 core promoter, leading to increased histone H4 acetylation and a loosening of nucleosomal-DNA interactions allowing "opening" of the chromatin structure and increased association of c-Jun and ATF-2. These changes are mediated through NFκB- and p38-dependent pathways. Ultimately, these events culminate in increasing ITGB8 transcription, αvβ8 surface expression, and αvβ8-mediated TGFβ activation.

8 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Integrin-associated signaling is a crucial signaling network in mammalian cells. Thousands of molecules are involved in this signaling network. For example, the RTK, Src-family kinase, Ras, Wnt-, Notch-, and Raft/caveolae-mediated signaling pathways are related to integrin signaling. Integrin signaling is also associated with direct involvement of lipid rafts. Tumor formation, angiogenesis, metastasis, and attachment to distant tissues are largely associated with integrin signaling. Recent evidence has indicated that integrin expression and its functions are tightly regulated by epigenetic mechanisms (modifications of DNA and histones). Aberrations in these epigenetic regulation patterns are frequently associated with the development of various diseases, including cancer. In this review, we discuss influences of integrin signaling along with their epigenetic relationship on other signals of a normal functioning cell and its dysregulation in cancer.
    Full-text · Article · Dec 2011 · CANCER AND METASTASIS REVIEW
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Eviction or destabilization of nucleosomes from chromatin is a hallmark of functional regulatory elements in eukaryotic genomes. Historically identified by nuclease hypersensitivity, these regulatory elements are typically bound by transcription factors or other regulatory proteins. FAIRE (formaldehyde-assisted isolation of regulatory elements) is an alternative approach to identify these genomic regions and has proven successful in a multitude of eukaryotic cell and tissue types. Cells or dissociated tissues are cross-linked briefly with formaldehyde, lysed and sonicated. Sheared chromatin is subjected to phenol/chloroform extraction and the isolated DNA, typically encompassing 1-3% of the human genome, is purified. We provide guidelines for quantitative analysis by PCR, microarrays or next-generation sequencing. Regulatory elements enriched by FAIRE have high concordance with those identified by nuclease hypersensitivity or chromatin immunoprecipitation (ChIP), and the entire procedure can be completed in 3 d. FAIRE has low technical variability, which allows its usage in large-scale studies of chromatin from normal or diseased tissues.
    Full-text · Article · Feb 2012 · Nature Protocol
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An increasing number of transcription factors have been shown to elicit oncogenic and tumor suppressor activities, depending on the tissue and cell context. Activating transcription factor 2 (ATF2; also known as cAMP-dependent transcription factor ATF-2) has oncogenic activities in melanoma and tumor suppressor activities in non-malignant skin tumors and breast cancer. Recent work has shown that the opposing functions of ATF2 are associated with its subcellular localization. In the nucleus, ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. ATF2 can also translocate to the cytosol, primarily following exposure to severe genotoxic stress, where it impairs mitochondrial membrane potential and promotes mitochondrial-based cell death. Notably, phosphorylation of ATF2 by the epsilon isoform of protein kinase C (PKCε) is the master switch that controls its subcellular localization and function. Here, we summarize our current understanding of the regulation and function of ATF2 in both subcellular compartments. This mechanism of control of a non-genetically modified transcription factor represents a novel paradigm for 'oncogene addiction'.
    Preview · Article · Jun 2012 · Journal of Cell Science
Show more