Loss of MHC class II inducibility in hyperplastic tissue in Rb-defective mice

Eason, Donna D.; Coppola, Domenico; Livingston, Sandra; Shepherd, Alexander T; Blanck, George

doi:10.1016/s0304-3835(01)00603-6

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…One tumor suppressor activated by IFN is Rb [7], [8], a protein that controls cell cycle or differentiation and that may have a role in modulation of immune functions [2], [3], [4], [5], [18], [19], [20], [21].…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its classical role in the control of cell progression, the influence of Rb on immune response was also proposed. In this sense, a significant fraction of genes associated with processes related to immune responses, particularly those induced by pathogens or injuries including cell surface molecules, complement factors and genes involved in interferon (IFN) system, are down-regulated in Rb knockout cells [2], [3], [4], [5]. In addition, transforming viral agents contain oncoproteins that inactivate Rb and strikingly, these tumor cells are more susceptible to virus infection than normal cells.…”

Section: Introductionmentioning

confidence: 99%

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Activation of NF-kB Pathway by Virus Infection Requires Rb Expression

et al. 2009

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The retinoblastoma protein Rb is a tumor suppressor involved in cell cycle control, differentiation, and inhibition of oncogenic transformation. Besides these roles, additional functions in the control of immune response have been suggested. In the present study we investigated the consequences of loss of Rb in viral infection. Here we show that virus replication is increased by the absence of Rb, and that Rb is required for the activation of the NF-kB pathway in response to virus infection. These results reveal a novel role for tumor suppressor Rb in viral infection surveillance and further extend the concept of a link between tumor suppressors and antiviral activity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of NF-kB Pathway by Virus Infection Requires Rb Expression

et al. 2009

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“…There are also data that RB can function as a transcriptional activator in specific settings. For example, it has been previously observed that RB-null cells have reduced expression of major histocompatibility complex class I and II proteins, and that restoration of RB induces the expression of these genes (Lu et al, 1994;Zhu et al, 1999;Eason et al, 2001). Additionally, RB can bind to JunD, NeuroD1, CBFA1, PU.1 and the androgen receptor to mediate transcription factor activation (Thomas et al, 2001;Xin et al, 2003;Iavarone et al, 2004;Batsche et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The influence of RB loss on immune response has been previously proposed. In studies investigating interferon g-regulated gene expression, there is a deficit in the induction of specific interferon-inducible genes in RB-deficient cells (Lu et al, 1994;Osborne et al, 1997;Zhu et al, 1999;Eason et al, 2001). This change in gene expression has been attributed to changes in chromatin structure and regulation of Oct-1 function (Osborne et al, 1997(Osborne et al, , 2004.…”

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confidence: 99%

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

et al. 2007

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Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of ciselements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB.Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.

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“…The potential impact of MHCII expression on solid tumor cells received increased interest when it became apparent over two decades ago that mutations specific to tumorigenesis interfered with MHCII induction by interferon-γ (IFN-γ) (1)(2)(3)(4)(5)(6)(7)(8)(9). As one example, a lack of retinoblastoma tumor suppressor protein leads to over expression of the pro-proliferative protein, YY1, which in turn is part of a repressive complex that maintains histone deacetylase activity at the MHCII promoter, thereby blocking the assembly of MHCII enhanceosome proteins, including the highly specific MHCII enhanceosome proteins, RFXANK, RFXAP, RFX5 and CIITA (10,11).…”

Section: Introductionmentioning

confidence: 99%

MHC class II associated stomach cancer mutations correlate with lack of subsequent tumor development

Yavorski

Blanck

2017

mol clin onc

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Abstract. The role of tumor cell expression of major histocompatibility class II (MHCII) has been controversial, with evidence indicating that tumor cell expression of MHCII may lead to an anti-tumor immune response and to tumor cell apoptosis and that MHCII has pro-tumorigenic functions. The cancer genome atlas (TCGA) indicates numerous deleterious mutations for the highly specific, MHCII transcriptional activation proteins, RFX5, RFXAP, RFXANK and CIITA. Also, mutations in the non-polymorphic, human leukocyte antigen (HLA)-DRA gene, which encodes the heavy chain for the most prominent human MHCII molecule, HLA-DR, are common. For many, if not most TCGA cancer datasets, the MHCII specific mutations do not associate with clinical outcomes. However, stomach carcinoma represents an exception, where the data indicate that MHCII-specific mutations are associated with a more favorable outcome. These data raise the question of whether stomach cancer mutations represent effective haploinsufficiency or whether mutations that are associated with a favorable outcome occur with other stomach cancer molecular features that limit the function of the two alleles that represent these MHCII-related proteins.

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Loss of MHC class II inducibility in hyperplastic tissue in Rb-defective mice

Cited by 6 publications

References 30 publications

Activation of NF-kB Pathway by Virus Infection Requires Rb Expression

Activation of NF-kB Pathway by Virus Infection Requires Rb Expression

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

MHC class II associated stomach cancer mutations correlate with lack of subsequent tumor development

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