pRB is required for interferon-γ-induction of the MHC class II Aβ gene

Zhu, Xin Sheng; Pattenden, Samantha G.; Bremner, Rod

doi:10.1038/sj.onc.1202876

Cited by 26 publications

(20 citation statements)

References 92 publications

(70 reference statements)

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“…Although unexpected, there is precedent for the lack of a requirement for a transactivator in determining the chromatin structure of the target promoters. For example, major histocompatibility complex class II genes can be induced in a retinoblastoma tumor suppressor protein-dependent fashion (65,66). In retinoblastoma Ϫ/Ϫ cells these genes are not induced although the promoter region is constitutively open as defined by DNase I hypersensitivity (67).…”

Section: Fig 6 P53 Interacts With P53 Res In Dna-damaged Hct116 Celmentioning

confidence: 99%

Constitutive DNase I Hypersensitivity of p53-Regulated Promoters

Braastad

Han

Hendrickson

2003

Journal of Biological Chemistry

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The ability of p53 to alter, at the transcriptional level, the gene expression of downstream targets is critical for its role as a tumor suppressor. Most models of p53 activation postulate the stepwise recruitment by p53 of coactivators, histone acetyltransferases, and/or chromatin remodeling factors to a promoter region to facilitate the subsequent access of the general transcriptional machinery required for transcriptional induction. We demonstrate here, however, that the promoter regions for the p53 target genes, p21, 14-3-3, and KARP-1, exist in a constitutively open conformation that is readily accessible to DNase I. This conformation was not altered by DNA damage or by whether p53 was present or absent in the cell. In contrast, p53 response elements, which resided outside the immediate promoter regions, existed within DNase I-resistant chromatin domains. Thus, p53 activation of downstream target genes occurs without p53 inducing chromatin alterations detectable by DNase I accessibility at either the promoter or the response element. As such, these data support models of p53 activation that do not require extensive chromatin alterations to support cognate gene expression.The differential chromatin structure and nuclease accessibility at a promoter region has long been recognized as a key distinguishing feature between active and inactive genes (reviewed in Ref. 1). Almost invariably, the promoter regions of active genes are marked experimentally by hypersensitivity to restriction endonucleases (2, 3) or, more commonly, DNase I (4). Although this hypersensitivity can be caused by torsional or topological stress in the DNA and distortions in the chromatin structure resulting from transcription factor binding, it is generally caused by the absence of nucleosomes or their remodeling (1, 4). The paucity of nucleosomes, in turn, is a direct consequence of the repressive effect that nucleosomes have on the transcriptional machinery and the requirement to alleviate that effect for productive transcription to occur (5-7). Thus, inactive genes usually have promoters that are nucleosomal, are insensitive to DNase I, and are regarded as being in a closed confirmation whereas active genes usually have core promoters that are nucleosome-free, hypersensitive to DNase I, and in an open configuration. Consequently, one of the hallmarks of gene induction mechanisms is the remodeling of the nucleosomal architecture of a promoter as it is activated (5, 6, 8).Enormous strides have been made in the last decade in understanding transcriptional activation at the chromatin level. In particular, the activation of expression of many, although not all (9 -11), inducible eukaryotic genes is consistent with what can collectively be called recruitment models of gene activation (3, 7, 8) (reviewed in Ref. 12). These models usually require, in response to some extracellular cue, the induction of a specific transcription factor and the subsequent interaction of that factor with its cognate response element, which is invariably a cis-acting ...

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Section: Fig 6 P53 Interacts With P53 Res In Dna-damaged Hct116 Celmentioning

confidence: 99%

Constitutive DNase I Hypersensitivity of p53-Regulated Promoters

Braastad

Han

Hendrickson

2003

Journal of Biological Chemistry

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“…However, with few exceptions, it is not clear how or to what extent human tumor cells lose a functional IFN-␥ signaling pathway as part of tumorigenesis. In the most well understood case, the loss of Rb is associated with loss of MHC class II inducibility in cell lines in culture (37) and in Rb-defective mice (38). The loss of functional IFN-␥ signaling could impact on tumor Ag presentation through loss of MHC class II inducibility, leading to a reduced antitumor immune response (19,36,39,40), or on the susceptibility of tumor cells to undergo apoptosis (41)(42)(43).…”

Section: Transient Stat1 Activation and Tumorigenesismentioning

confidence: 99%

High Level Class IItrans-Activator Induction Does Not Occur with Transient Activation of the IFN-γ Signaling Pathway

Eason¹,

Blanck

2001

The Journal of Immunology

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Gene activation in early development is highly dependent on precise concentrations of trans-acting factors for the activation of different genes at differing points in the embryo. Thus, not only is the presence or absence of a particular trans-activator or repressor relevant in determining gene activation, but also the concentration of the regulatory protein must be above or below a certain threshold for proper gene regulation. Signaling pathways in somatic cells are thought to represent cascades of on/off switches, mediated most commonly by phosphorylation. Here we demonstrate a quantitative mechanism for regulating the level of a component of the IFN-γ signaling pathway that in effect represents the differential sensitivities of STAT1, IFN-regulatory factor-1, and class II trans-activator (CIITA) to IFN-γ. Unlike developmental gene regulation, in which specificity of gene activation is a function of regulatory protein concentrations, specificity of gene activation in the IFN-γ signaling pathway is regulated by the duration of the activation of the primary IFN-γ-regulatory protein, STAT1. This result most likely explains previously reported data indicating that a minimum amount of IFN-γ is required for MHC class II gene activation despite the fact that the level of the IFN-γ-inducible factor directly required for MHC class II induction, CIITA, directly correlates with the level of MHC class II expression. The induction of a high level of CIITA is dependent on sustained IFN-γ signaling. The possible implications of this result for tumorigenesis are discussed.

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“…Rb forms a pentameric complex that includes tal-1, which downmodulates c-kit expression and presumably other erythroid genes during erythropoiesis (Vitelli et al, 2000). Rb is also required for interferon-gammainduction of the MHC class II gene (Zhu et al, 1999). Third, ectopic expression of Rb in Rb-de®cient cells can induce di erentiation in vitro (Sellers et al, 1998).…”

Section: Effect Of Rb On Lens Specific Gene Expressionmentioning

confidence: 99%

E2F1 mediates ectopic proliferation and stage-specific p53-dependent apoptosis but not aberrant differentiation in the ocular lens of Rb deficient fetuses

Liu

Zacksenhaus

2000

Oncogene

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The retinoblastoma tumor suppressor, Rb, is a transcription cofactor that controls cell proliferation, survival and di erentiation. Mutant mouse embryos lacking Rb exhibit ectopic proliferation and apoptosis that are mediated in some tissues by E2F1, a major partner of Rb, and by the p53 tumor suppressor. Whether E2F1 and p53 also mediate the di erentiation defects in Rb mutant embryos is, however, not clear. Here we show that partially rescued mgRb:Rb7/7 mutant fetuses exhibit ectopic lens epithelial cell proliferation, apoptosis and severe cataract. The abnormal cell proliferation and apoptosis were signi®cantly suppressed in the lens of compound mutant fetuses lacking both Rb and E2F1 at embryonic day (E) E15.5. Interestingly however, at E18.5, only ectopic proliferation, not apoptosis, was dramatically reduced in mgRb:Rb7/7:E2F17/7 lenses. In contrast, p53 did not exert such a stage-speci®c e ect and apoptosis was invariably suppressed in mgRb:Rb7/7:p537/7 composite mutant lenses throughout embryogenesis. Using RT ± PCR and in situ hybridization analyses, we identi®ed a subset of lens speci®c genes, most notably the late di erentiation marker ®lensin, which were not properly induced during lens development in mgRb:Rb7/7 fetuses. Remarkably, despite the inhibition of cell proliferation and apoptosis, the degeneration of lens ®bers and aberrant expression of ®lensin were only marginally corrected in mgRb:Rb7/7:E2F17/7 fetuses at E15.5 but not at all at E18.5 or in mgRb:Rb7/7:p537/7 mutant fetuses. Thus, inactivation of E2F1 reduces ectopic cell proliferation and stage-speci®c p53-dependent apoptosis but does not rescue the di erentiation defects associated with loss of Rb during lens development.

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pRB is required for interferon-γ-induction of the MHC class II Aβ gene

Cited by 26 publications

References 92 publications

Constitutive DNase I Hypersensitivity of p53-Regulated Promoters

Constitutive DNase I Hypersensitivity of p53-Regulated Promoters

High Level Class IItrans-Activator Induction Does Not Occur with Transient Activation of the IFN-γ Signaling Pathway

E2F1 mediates ectopic proliferation and stage-specific p53-dependent apoptosis but not aberrant differentiation in the ocular lens of Rb deficient fetuses

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