scholarly journals Negative regulation of the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells via a retinoic acid response element.

1992 ◽  
Vol 66 (12) ◽  
pp. 6979-6988 ◽  
Author(s):  
A Kralli ◽  
R Ge ◽  
U Graeven ◽  
R P Ricciardi ◽  
R Weinmann
Keyword(s):  
Major Histocompatibility Complex ◽  
Retinoic Acid ◽  
Major Histocompatibility Complex Class ◽  
Adenovirus Type ◽  
Negative Regulation ◽  
Transformed Cells ◽  
Complex Class ◽  
Response Element ◽  
Retinoic Acid Response Element ◽  
Histocompatibility Complex

scholarly journals Evidence for the involvement of a nuclear NF-kappa B inhibitor in global down-regulation of the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells.

1996 ◽  
Vol 16 (1) ◽  
pp. 398-404 ◽  
Author(s):  
X Liu ◽  
R Ge ◽  
R P Ricciardi
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Adenovirus Type ◽  
Class I ◽  
Transformed Cells ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Nf Kappa B ◽  
Down Regulation ◽  
Histocompatibility Complex

Diminished expression of major histocompatibility complex class I antigens on the surface of adenovirus type 12 (Ad12)-transformed cells contributes to their high tumorigenic potential by enabling them to escape immune recognition by cytotoxic T lymphocytes. This low class I antigen expression is due to a block in class I transcription, which is mediated by Ad12 E1A. Genetic analysis has shown that the class I enhancer is the target for transcriptional down-regulation. In this study, we show that the ability of the R1 element of the class I enhancer to stimulate transcription is greatly reduced in Ad12-transformed cells. The loss of functional activity by the R1 element was attributed to loss of binding by the NF-kappa B p50-p65 heterodimer. NF-kappa B binding appears to be blocked within the nucleus rather than at the level of nuclear translocation. Significantly, NF-kappa B binding activity could be recovered from the nuclear extracts of Ad12-transformed cells following detergent treatment, suggesting that the block is mediated through a nuclear inhibitor present in the Ad12-transformed cells. These results, taken together with the fact that the R2 element of the class I enhancer exhibits strong binding to the transcriptional repressor COUP-TF, suggest that the class I enhancer is globally down-regulated in Ad12-transformed cells.

scholarly journals In Adenovirus Type 12 Tumorigenic Cells, Major Histocompatibility Complex Class I Transcription Shutoff Is Overcome by Induction of NF-κB and Relief of COUP-TFII Repression

2002 ◽  
Vol 76 (7) ◽  
pp. 3212-3220 ◽  
Author(s):  
Shihe Hou ◽  
Hancheng Guan ◽  
Robert P. Ricciardi
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Nuclear Translocation ◽  
Adenovirus Type ◽  
Class I ◽  
Transformed Cells ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Tnf Α

ABSTRACT The surface levels of major histocompatibility complex class I antigens are diminished on tumorigenic adenovirus type 12 (Ad12)-transformed cells, enabling them to escape from immunosurveillant cytotoxic T lymphocytes (CTLs). This is due to the down-regulation of the class I transcriptional enhancer, in which there is strong binding of the repressor COUP-TFII and lack of binding of the activator NF-κB. Even though NF-κB (p65/p50) translocates to the nuclei of Ad12-transformed cells, it fails to bind to DNA efficiently due to the hypophosphorylation of the p50 subunit. In this study, tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) were shown to promote degradation of the NF-κB cytoplasmic inhibitor IκBα and permit the nuclear translocation of a phosphorylated form of NF-κB that is capable of binding DNA. Interestingly, when Ad12-transformed cells were treated with TNF-α or IL-1β, class I gene transcription substantially increased when transcriptional repression by COUP-TFII was blocked. This indicates that in cytokine-treated Ad12-transformed cells, COUP-TFII is able to repress activation of class I transcription by newly nucleus-localized NF-κB. Our results suggest that Ad12 likely employs a “fail-safe” mechanism to ensure that the transcription of class I genes remains tightly repressed under various physiological conditions, thus providing tumorigenic Ad12-transformed cells with a means of escaping CTL recognition and lysis.

scholarly journals Reduced Phosphorylation of p50 Is Responsible for Diminished NF-κB Binding to the Major Histocompatibility Complex Class I Enhancer in Adenovirus Type 12-Transformed Cells

1999 ◽  
Vol 19 (3) ◽  
pp. 2169-2179 ◽  
Author(s):  
David B. Kushner ◽  
Robert P. Ricciardi
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Adenovirus Type ◽  
Class I ◽  
Transformed Cells ◽  
Complex Class ◽  
Transformed Cell ◽  
Histocompatibility Complex ◽  
Nuclear Extracts

ABSTRACT Reduced cell surface levels of major histocompatibility complex class I antigens enable adenovirus type 12 (Ad12)-transformed cells to escape immunosurveillance by cytotoxic T lymphocytes (CTL), contributing to their tumorigenic potential. In contrast, nontumorigenic Ad5-transformed cells harbor significant cell surface levels of class I antigens and are susceptible to CTL lysis. Ad12 E1A mediates down-regulation of class I transcription by increasing COUP-TF repressor binding and decreasing NF-κB activator binding to the class I enhancer. The mechanism underlying the decreased binding of nuclear NF-κB in Ad12-transformed cells was investigated. Electrophoretic mobility shift assay analysis of hybrid NF-κB dimers reconstituted from denatured and renatured p50 and p65 subunits from Ad12- and Ad5-transformed cell nuclear extracts demonstrated that p50, and not p65, is responsible for the decreased ability of NF-κB to bind to DNA in Ad12-transformed cells. Hypophosphorylation of p50 was found to correlate with restricted binding of NF-κB to DNA in Ad12-transformed cells. The importance of phosphorylation of p50 for NF-κB binding was further demonstrated by showing that an NF-κB dimer composed of p65 and alkaline phosphatase-treated p50 from Ad5-transformed cell nuclear extracts could not bind to DNA. These results suggest that phosphorylation of p50 is a key step in the nuclear regulation of NF-κB in adenovirus-transformed cells.

scholarly journals Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription.

1993 ◽  
Vol 13 (1) ◽  
pp. 588-599 ◽  
Author(s):  
N Nelson ◽  
M S Marks ◽  
P H Driggers ◽  
K Ozato
Keyword(s):  
Major Histocompatibility Complex ◽  
Retinoic Acid ◽  
Major Histocompatibility Complex Class ◽  
Binding Protein ◽  
Consensus Sequence ◽  
Interferon Regulatory Factor ◽  
Chloramphenicol Acetyltransferase ◽  
Complex Class ◽  
Regulatory Factor ◽  
Histocompatibility Complex

We previously isolated a cDNA clone encoding interferon consensus sequence-binding protein (ICSBP), a member of the interferon regulatory factor (IRF) family, that binds to the interferon (IFN)-stimulated response element (ISRE) of many IFN-regulated genes. In this investigation, we studied the functional role of ICSBP by transient cotransfection of ICSBP cDNA with IFN-responsive reporter genes into the human embryonal carcinoma cell line N-Tera2. These cells were shown not to express ICSBP or IRF-2, thus allowing functional analysis of transfected cDNAs. Cotransfection of ICSBP into cells treated with retinoic acid or any of the IFNs (alpha, beta, or gamma) repressed expression of a chloramphenicol acetyltransferase reporter driven by the major histocompatibility complex class I gene promoter. Similarly, ICSBP repressed expression of chloramphenicol acetyltransferase reporters driven by the ISREs of the 2'-5' oligoadenylate synthetase, guanylate-binding protein, and ISG-15 genes in IFN-treated cells. The repression was dependent on the presence of the ISRE in the reporter. Deletion analysis showed that the putative N-terminal DNA binding domain of ICSBP by itself is capable of mediating the repression. Using the same cotransfection conditions as for ICSBP, a similar repression of these reporters was observed with IRF-2. Finally, ICSBP repressed the IRF-1-mediated induction of major histocompatibility complex class I and IFN-beta reporters in the absence of IFN or retinoic acid. Taken together, these results suggest that ICSBP is a negative regulatory factor capable of repressing transcription of target genes induced by IFN, retinoic acid, or IRF-1.

scholarly journals The N Terminus of Adenovirus Type 12 E1A Inhibits Major Histocompatibility Complex Class I Expression by Preventing Phosphorylation of NF-κB p65 Ser276 through Direct Binding

2010 ◽  
Vol 84 (15) ◽  
pp. 7668-7674 ◽  
Author(s):  
Junfang Jiao ◽  
Hancheng Guan ◽  
Andrew M. Lippa ◽  
Robert P. Ricciardi
Keyword(s):  
Amino Acids ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Adenovirus Type ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
N Terminus

ABSTRACT The immune-escape strategy employed by human oncogenic adenovirus type 12 (Ad12) involves downregulation of major histocompatibility complex class I (MHC-I) transcription by disabling the transactivator NF-κB (p50/p65). This is accomplished by the Ad12 E1A protein (E1A-12), which prevents NF-κB from becoming phosphorylated by the protein kinase A catalytic subunit (PKAc). In this study, we examined the interactions between E1A-12 and NF-κB. Our data show that an E1A-12 mutant retaining the N-terminal 66 amino acids was as effective as the wild-type E1A-12 protein (266 amino acids) in binding p65, preventing phosphorylation of p65-Ser276, and inhibiting transactivation. In contrast, the nontumorigenic adenovirus type 5 E1A protein (E1A-5) and other E1A-12 mutants lacking the N-terminal regions were severely defective in these activities. Further studies revealed that an N-terminal peptide consisting of residues 1 to 40 of E1A-12 was able to associate directly with p65 in vitro and prevent PKAc from phosphorylating p65-Ser276. In the absence of the N terminus, there is an almost complete loss of E1A-12 binding to p65. These findings provide solid evidence for the role of the E1A-12 N terminus as an NF-κB binding domain. Significantly, this study indicates that the E1A-12 N terminus prevents PKAc from gaining access to p65 to account for Ser276 hypophosphorylation. The E1A-12 N terminus interaction with p65 serves as a key explanation of how Ad12 downregulates MHC-I transcription and contributes to oncogenesis by escaping cytotoxic T lymphocytes.

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