Class II Major Histocompatibility Complex Transactivator (CIITA) Inhibits Matrix Metalloproteinase-9 Gene Expression

Nozell, Susan E.; Ma, Zhendong; Wilson, Cynthia; Shah, Reesha C.; Benveniste, Etty N.

doi:10.1074/jbc.m403738200

Cited by 44 publications

(37 citation statements)

References 41 publications

(77 reference statements)

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“…This finding prompted us to determine whether squelching of CBP, p300, or PCAF could account for the observed inhibition of Tax-2 by CIITA. These HATs were attractive candidates in light of the fact that their squelching seems to be a common mechanism by which CIITA mediates gene suppression (69)(70)(71)(72). We found that direct sequestration of the above cofactors was not the primary mechanism by which CIITA causes suppression of Tax-2 transactivating function.…”

Section: Discussionmentioning

confidence: 74%

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y

Tosi

Pilotti

Mortara

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The master regulator of MHC-II gene transcription, class II transactivator (CIITA), acts as a potent inhibitor of human T cell leukemia virus type 2 (HTLV-2) replication by blocking the activity of the viral Tax-2 transactivator. Here, we show that this inhibitory effect takes place at the nuclear level and maps to the N-terminal 1-321 region of CIITA, where we identified a minimal domain, from positions 64 -144, that is strictly required to suppress Tax-2 function. Furthermore, we show that Tax-2 specifically cooperates with cAMP response element binding protein-binding protein (CBP) and p300, but not with p300͞CBP-associated factor, to enhance transcription from the viral promoter. This finding represents a unique difference with respect to Tax-1, which uses all three coactivators to transactivate the human T cell leukemia virus type 1 LTR. Direct sequestering of CBP or p300 is not the primary mechanism by which CIITA causes suppression of Tax-2. Interestingly, we found that the transcription factor nuclear factor Y, which interacts with CIITA to increase transcription of MHC-II genes, exerts a negative regulatory action on the Tax-2-mediated HTLV-2 LTR transactivation. Thus, CIITA may inhibit Tax-2 function, at least in part, through nuclear factor Y. These findings demonstrate the dual defensive role of CIITA against pathogens: it increases the antigen-presenting function for viral determinants and suppresses HTLV-2 replication in infected cells. Tax-2 MHC class II ͉ viral replication ͉

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Section: Discussionmentioning

confidence: 74%

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y

Tosi

Pilotti

Mortara

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells were grown overnight in complete medium, and then cell lysates were collected as described above. Five hundred micrograms of total protein were immunoprecipitated with 5 g of anti-p65 monoclonal antibody and analyzed by immunoblotting with anti-Flag antibody as previously described (26). Where indicated, cells were plated at 6 ϫ 10 7 cells per 15-cm plate in complete medium, in the absence or presence of Tet.…”

Section: Methodsmentioning

confidence: 99%

“…The U251-MG, U118-MG, and U87-MG glioma cell lines were obtained from ATCC and maintained as previously described (5,25,40). U251-MG cells that stably express the Tet repressor (TetR) protein and inducibly express F-ING4 or shRNA specific for p65 (sh-p65), and U118-MG cells that stably express the TetR and that inducibly express shRNA specific for ING4 (shING4) were generated as previously described (26).…”

Section: Methodsmentioning

confidence: 99%

The ING4 Tumor Suppressor Attenuates NF-κB Activity at the Promoters of Target Genes

Nozell¹,

Laver²,

Moseley³

et al. 2008

Molecular and Cellular Biology

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133

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The NF-B family mediates immune and inflammatory responses. In many cancers, NF-B is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is a tumor suppressor that is absent or mutated in several cancers. Herein, we demonstrate that in human gliomas, NF-B is constitutively activated, ING4 expression is negligible, and NF-B-regulated gene expression is elevated. We demonstrate that an ING4 and NF-B interaction exists but does not prevent NF-B activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-B bind simultaneously at NF-B-regulated promoters, and this binding correlates with reductions in p65 phosphorylation, p300, and the levels of acetylated histones and H3-Me3K4, while enhancing the levels of HDAC-1 at these promoters. Using a knockdown approach, we correlate reductions in ING4 protein levels with increased basal and inducible NF-B target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-B molecules that are bound to target gene promoters.

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“…Overexpression of CBP in the presence of CIITA allowed reactivation of a Col1a1 reporter, indicating that CIITA represses the Col1a1 promoter by sequestering CBP (64). The CIITA-mediated repression of matrix metalloproteinase 9 (MMP-9) is also mediated by the sequestration of CBP by CIITA (36). Another group has shown that CIITA negatively regulates Ctse by inhibiting a related histone acetyltransferase, p300, required for CtseE promoter activity (61).…”

mentioning

confidence: 99%

Gamma Interferon Modulates Myogenesis through the Major Histocompatibility Complex Class II Transactivator, CIITA

Londhe

Davie

2011

Molecular and Cellular Biology

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Gamma interferon (IFN-␥) is an inflammatory cytokine that has complex effects on myogenesis. Here, we show that the IFN-␥-induced inhibition of myogenesis is mediated by the major histocompatibility complex (MHC) class II transactivator, CIITA, which binds to myogenin and inhibits its activity. In IFN-␥-treated myoblasts, the inhibition of muscle-specific genes includes the expression of myogenin itself, while in myotubes, myogenin expression is unaffected. Thus, CIITA appears to act by both repressing the expression and inhibiting the activity of myogenin at different stages of myogenesis. Stimulation by IFN-␥ in skeletal muscle cells induces CIITA expression as well as MHC class II gene expression. The IFN-␥-mediated repression is reversible, with myogenesis proceeding normally upon removal of IFN-␥. Through overexpression studies, we confirm that the expression of CIITA, independent of IFN-␥, is sufficient to inhibit myogenesis. Through knockdown studies, we also demonstrate that CIITA is necessary for the IFN-␥-mediated inhibition of myogenesis. Finally, we show that CIITA, which lacks DNA binding activity, is recruited to muscle-specific promoters coincident with reductions in RNA polymerase II recruitment. Thus, this work reveals how IFN-␥ modulates myogenesis and demonstrates a key role for CIITA in this process.Gamma interferon (IFN-␥) is an inflammatory cytokine that was first identified as an antiviral factor. IFN-␥ is a pleiotropic cytokine that regulates different immune responses and influences many physiological processes. Many studies have also shown that IFN-␥ influences skeletal muscle homeostasis and repair. Transient administration of exogenous IFN-␥ has been shown to improve healing of skeletal muscle and limit fibrosis (14). Endogenous IFN-␥ is required for efficient muscle regeneration, as mice lacking IFN-␥ show impaired muscle regeneration following cardiotoxin-induced damage (6). Expression of IFN-␥ is robust in proliferating C2C12 cells, but expression is diminished in differentiated C2C12 cells (6). Exogenous IFN-␥ influences the proliferation and differentiation of cultured myoblasts and appears to have a direct role on gene expression (25,26,28,48).Myoblasts have been shown to express immunological properties such as the complement component of both the classical and alternative pathways and major histocompatibility complex (MHC) genes. Exogenous IFN-␥ treatment has been shown to increase the expression of MHC class II genes, complement C components, intracellular adhesion molecule (Icam1), chemokine (C-C motif) ligand 5 (Ccl5; RANTES), chemokine (C-C motif) ligand 2 (Ccl2), and chemokine (C-X-C motif) ligand 10 (Cxcl10; Ip10) (15,25,28,48). It is not currently known how IFN-␥ mediates these transcriptional effects in myoblasts.The positive role for IFN-␥ established in muscle healing and repair suggests that this cytokine plays an important role in muscle biology. However, IFN-␥ signaling is likely to be tightly regulated, as negative effects of IFN-␥ have been observed as well. Whe...

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Class II Major Histocompatibility Complex Transactivator (CIITA) Inhibits Matrix Metalloproteinase-9 Gene Expression

Cited by 44 publications

References 41 publications

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y

The ING4 Tumor Suppressor Attenuates NF-κB Activity at the Promoters of Target Genes

Gamma Interferon Modulates Myogenesis through the Major Histocompatibility Complex Class II Transactivator, CIITA

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