IGF-1 down-regulates IFN-γR2 chain surface expression and desensitizes IFN-γ/STAT-1 signaling in human T lymphocytes

Bernabei, Paola; Bosticardo, Marita; Losana, Giuliana; Regis, Gabriella; Paola, Francesca Di; Angelis, Stefania De; Giovarelli, Mirella; Novelli, Francesco

doi:10.1182/blood-2003-01-0100

Cited by 45 publications

(57 citation statements)

References 47 publications

(43 reference statements)

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“…The first evidence for a role in transcription came from studies in yeast in which the fusion of the COOH-terminal domain of BRCA1 to a Gal4 DNA binding domain resulted in the activation of a Gal4 reporter construct. This activation was abrogated on the introduction of diseaserelated mutations in the COOH-terminal domain as well as the deletion of the last 11 amino acids of BRCA1 (6)(7)(8). These results were supported by the observation that the BRCA1 COOHterminal domain was highly acidic, a common feature of transcription factors (9).…”

Section: Introductionsupporting

confidence: 75%

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

Buckley

Hosey

Gorski

et al. 2007

Molecular Cancer Research

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BRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-;, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-;. We also show that the induction of IRF-7 by BRCA1 and IFN-; is dependent on the type I IFNs, IFN-A and IFN-B. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-;. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-A and IFN-B in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-; regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling. (Mol Cancer Res 2007;5(3):261 -70)

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Section: Introductionsupporting

confidence: 75%

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

Buckley

Hosey

Gorski

et al. 2007

Molecular Cancer Research

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“…Despite the prolonged STAT1 activation elicited by IFN-g in ST4-S1 cells, MHC I molecules induction was unchanged, suggesting that low levels of active STAT1 are sufficient to achieve maximal induction. This observation fits with the data showing that IFN-g optimally induces the upregulation of MHC I in human malignant T cells cultured in the presence of serum, 23 an experimental condition that promotes IFN-gR2 internalization and weak and transient STAT1 activation by IFN-g. 18,21,24 Importantly, IL-6 was able to induce apoptosis in ST4-S1 cells more efficiently than IFN-g, correlating with the growth inhibition activity observed in vivo. Indeed, although IFN-g did not affect tumor growth, IL-6 treatment could delay the growth of ST4-S1 cells in SCID mice and in some cases even completely prevent it.…”

Section: Discussionmentioning

confidence: 74%

“…IFN-gdependent apoptosis is known to be strictly linked to the levels of IFN-gR2 expression. 15,18,24 In ST4-S1 cells, IFN-gR2 expression levels were as low as those of the ST4-WT and ST4-C control cells (data not shown), correlating with the limited Figure 4 Interleukin (IL)-6 can inhibit in vivo growth of ST4-S1 cells. Severe combined immunodeficient mice were inoculated subcutaneously with 10 Â 10 6 ST4-C (a) or ST4-S1 cells (b).…”

Section: Discussionmentioning

confidence: 75%

IL-6, but not IFN-γ, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing

et al. 2009

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STAT1 and STAT3 are the main mediators of the signaling of interferons (IFNs) and of gp130 cytokines, respectively. Neoplastic T lymphocytes frequently become resistant to the IFN-c/ STAT1 apoptotic pathway, often because of the downregulation of the IFN-cR2 receptor chain. Many studies suggest that crossregulation between different STATs, in particular between STAT1 and STAT3, may profoundly affect cytokine/growth factor signaling. Here, the function of STAT3 in the negative regulation of STAT1 apoptotic pathway was investigated by RNA interference-mediated STAT3 silencing in human malignant T lymphocytes. In STAT3-depleted cells, interleukin (IL)-6 acquired the capacity to induce apoptosis, correlating with prolonged STAT1 activation and the induction of major histocompatibility complex (MHC) class I expression. In contrast, in the absence of STAT3, IFN-c could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-c, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes transplanted into severe combined immunodeficient mice. Therefore, treatment with IL-6 and simultaneous STAT3 silencing may represent a potential therapeutic approach to control the expansion of IFN-c-unresponsive neoplastic T cells.

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“…Serum starvation enhances IFN-γR1 expression in T cells [54], and enhances IFN-γR2 cell surface expression in a variety of hematopoietic cell lines; this latter effect may be due to deprivation of IGF-1 [87]. Notably, enhanced activation of Stat1 occurred with the upregulation of IFN-γR2 and an IFN-γ-induced proapoptotic fate during serum starvation, establishing a three-way correlation, but how these pathways are linked was not certain.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the activation of Stat1 by the interferon-γ receptor complex

Krause¹,

He²,

Pestka

2006

Cell Res

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The activation of Stat1 by the interferon-gamma (IFN-γ) receptor complex is responsible for the transcription of a significant portion of IFN-γ induced genes. Many of these genes are responsible for the induction of an apoptotic state in response to IFN-γ. In the absence of Stat1 activation, IFN-γ instead induces a proliferative response. Modifying Stat1 activation by IFN-γ may have pharmacological benefits. We report that the rate of activation of Stat1 can be altered in HeLa cells by overexpressing either the IFN-γR1 chain or the IFN-γR2 chain. These alterations occur in hematopoietic cell lines: Raji cells and monocytic cell lines, which have average and above-average IFN-γR2 surface expression, activate Stat1 similarly to HeLa cells and HeLa cells overexpressing IFNγR2, respectively. The rapid Stat1 activation seen in HeLa cells can be inhibited by overexpressing a chimeric IFN-γR2 chain that does not bind Jak2 or (when high concentrations of IFN-γ are used) by overexpressing IFN-γR1. These data are consistent with a model in which the recruitment of additional Jak2 activity to a signaling complex accelerates the rate of Stat1 activation. We conclude that the rate of activation of Stat1 in cells by IFN-γ can be modified by regulating either receptor chain and speculate that pharmacological agents which modify receptor chain expression may alter IFN-γ receptor signal transduction.

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IGF-1 down-regulates IFN-γR2 chain surface expression and desensitizes IFN-γ/STAT-1 signaling in human T lymphocytes

Cited by 45 publications

References 47 publications

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

IL-6, but not IFN-γ, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing

Modulation of the activation of Stat1 by the interferon-γ receptor complex

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