Regulation of c-myc expression by IFN-γ through Stat1-dependent and -independent pathways

Ramana, Chilakamarti V.; Grammatikakis, Nicholas; Chernov, Mikhail V.; Nguyen, Hannah; Goh, Kunli; Williams, Bryan R.G.; Stark, George R.

doi:10.1093/emboj/19.2.263

Cited by 281 publications

(240 citation statements)

References 86 publications

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“…Studies employing wild type and Stat-1-null mouse embryonic fibroblasts identified a GAS element in the c-myc promoter that was necessary, but not sufficient, to suppress c-myc expression in wild-type cells. 22 Although a consensus exists that type I IFNs induce posttranscriptional modulation of c-myc mRNA, the molecular mechanism underlying this process is unclear. Different components of IFN-inducible RNA degradation machinery have been implicated in this action.…”

Section: Discussionmentioning

confidence: 99%

Defining the mechanism by which IFN-β dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35)

2006

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Type I interferons (IFN-a/-b) are capable of suppressing c-myc mRNA expression by modulating post-transcriptional processing. However, the molecular mechanism of this phenomenon is poorly understood. We previously established that human polynucleotide phosphorylase (hPNPase old-35 ), a type I IFNinducible 3 0 ,5 0 exoribonuclease involved in mRNA degradation, induces G 1 cell cycle arrest and eventually apoptosis by specifically degrading c-myc mRNA. We now demonstrate a close association between IFN-b-induced hPNPase old-35 upregulation and c-myc downregulation in human melanoma cells. Employing stable melanoma cell clones expressing hPNPase old-35 small inhibitory RNA, we demonstrate that hPNPase old-35 is a key molecule coupled with IFN-b-mediated downregulation of c-myc mRNA. Inhibition of hPNPase old-35 or overexpression of c-myc protects melanoma cells from IFN-bmediated growth inhibition, emphasizing the importance of hPNPase old-35 upregulation and consequent c-myc downregulation in IFN-b-induced growth inhibition and apoptosis induction. In these contexts, targeted overexpression of hPNPase old-35 might be a novel therapeutic strategy for c-myc-overexpressing and IFN-resistant tumors, such as melanomas.

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Section: Discussionmentioning

confidence: 99%

Defining the mechanism by which IFN-β dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35)

2006

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“…It has been reported that IFN-g induced cellular proteins, such as Stat-1, which could result in reduced expression of transgene. 17,30,31 Another study raised the possibility that IFN-g decreases the stability of several transcripts, including c-myc, c-fos and cftr. 18 However, such events would not be involved in the Mug-mediated suppression of transgene expression in the present study, because a single hydrodynamic injection of pCpGMug results in a sustained level of Mug in mouse serum, indicating that the transgene expression from pCpG-Mug is not suppressed by Mug.…”

Section: Inhibition Of Transgene Expression By Ifn-c L Zang Et Almentioning

confidence: 99%

Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy

et al. 2011

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Sustained expression of murine interferon (IFN)-g (Mug) was found to be effective in preventing tumor metastasis and atopic dermatitis in mouse models. However, our preliminary experiments suggested that the time-dependent decrease in the Mug expression was not compensated for by repeated injections of Mug-expressing plasmid. To identify the mechanism underlying this observation, a reporter plasmid was hydrodynamically injected into mice and the levels of the plasmid, mRNA and reporter protein were measured in mice receiving a pre-or co-administration of Mug-expressing plasmid. Co-injection of Mug-expressing plasmid had no significant effects on transgene expression from the reporter plasmid. In contrast, pre-injection of Mugexpressing plasmid greatly inhibited the expression of the reporter protein. Moreover, pre-injection of Mug-expressing plasmid also reduced the amount of the reporter plasmid in the nuclear fraction of mouse liver to o10%, and that of reporter mRNA to o1%. The degree of reduction in the expression of reporter protein was comparable with the reduction in mRNA. These results indicate that the difficulty in regaining the expression level of IFN-g is due to the impaired delivery of plasmid to the nucleus and to the suppression of transcription from the plasmid.

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“…For example, IFN-α can reduce c-myc mRNA stability in Daudi cells [48,49] but increases c-myc mRNA in murine fibroblasts [50]; IFN-β serine 17 can also inhibit cmyc mRNA stability in a colon carcinoma cell line [51]. While it is known that c-myc gene expression is decreased by IFN-γ in a Stat1-dependent manner in embryonic mouse fibroblasts [52], IFN-γ increases c-myc mRNA stability in a human breast cancer cell line [53]. Thus, IFNs have contra-indicatory roles on stability of c-myc mRNA, a transcriptional factor that regulates cell proliferation, and the response seems to be dependent on both of the type of IFN and the target cell.…”

Section: Role Of Ifn In Post-transcriptional Control Of Cellular Genementioning

confidence: 99%

Post-transcriptional control of the interferon system

Khabar

Young

2007

Biochimie

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The interferon (IFN) system is a well-controlled network of signaling, transcriptional, and posttranscriptional processes that orchestrate host defense against microbes. The IFN response comprises a multi-array of IFN-stimulated gene products that mediate a variety of biological processes designed to control infection and regulate specific immune responses. In this review, we focus on posttranscriptional mechanisms of gene regulation that occur during the course of IFN induction and during the response of cells to IFN. Post-transcriptional mechanisms involve different levels of regulation such as mRNA stability, alternative splicing, and translation. Such controls offer a fine tuning mechanism for efficient and rapid response and as a negative feedback control in IFN biosynthesis and response.

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Regulation of c-myc expression by IFN-γ through Stat1-dependent and -independent pathways

Cited by 281 publications

References 86 publications

Defining the mechanism by which IFN-β dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35)

Defining the mechanism by which IFN-β dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35)

Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy

Post-transcriptional control of the interferon system

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