Removal of a 67-base-pair sequence in the noncoding region of protooncogene fos converts it to a transforming gene.

Meijlink, Frits; Curran, Tom; Miller, A D; Verma, Inder M.

doi:10.1073/pnas.82.15.4987

Cited by 190 publications

(87 citation statements)

References 26 publications

(20 reference statements)

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“…It is generally believed that the natural expression of the c-fos gene does not transform cells, whereas inappropriate or overexpression of the c-fos gene may induce transformation of primary or established cell lines (Schiavi et al, 1992). It has been shown that the presence of the cfos ARE renders the c-fos mRNA short-lived (Shyu et al, 1989) and that the c-fos gene can be converted into a transforming oncogene when the ARE in the 3' UTR of c-fos mRNA is deleted (Lee et al, 1988;Meijlink et al, 1985;Raymond et al, 1989). Stabilization of c-fos mRNAs during oncogenesis has been demonstrated in tissue culture cells (Lee et al, 1988;Raymond et al, 1989) and in transgenic mice (RuÈ ther et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

et al. 1997

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Expression levels of human papillomavirus type 1 late genes are determined in part by an AU-rich inhibitory sequence in the 3' untranslated region on the late mRNAs. Fine mapping of the AU rich inhibitory sequence revealed that it mapped to a 57 nucleotide sequence, consisting of an AU-rich region containing two AUUUA motifs and a U-rich region containing three UUUUU motifs. An internal deletion showed that the Urich region was required for inhibition. Point mutations in the AUUUA-and UUUUU-motifs inactivated the inhibitory sequence. Analysis of the stability of mRNAs containing the AU-rich sequence in sense or anti-sense orientation showed that mRNAs containing the AU-rich sequence in sense orientation had reduced half life. Analysis of RNA-protein interactions revealed that binding to the inhibitory sequence of three poly(U) binding proteins (38, 44 and 46 kDa) correlated with inhibition and that the same proteins bind to the AU-rich mRNA instability element in the 3' untranslated region on the human c-fos mRNA. We speculate that the human papillomavirus late mRNAs, produced from several hundred copies of the virus genome present in infected cells, compete with the c-fos mRNAs for destabilizing cellular factors and that this may lead to elevated Fos protein levels in human papillomavirus infected cells

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Section: Discussionmentioning

confidence: 99%

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

et al. 1997

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“…with unspecific mRNA-degrading activities or transcriptional elongation blocks (Plet et al, 1995 Lee et al. 1988;Meijlink et al. 1985;Rahmsdorf et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

Strong and prolonged induction of c-jun and c-fos proto-oncogenes by photodynamic therapy

Kick

Messer²,

Plewig³

et al. 1996

Br J Cancer

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SummaryPhotodynamic therapy (PDT) is currently under investigation in phase II and III clinical studies for the treatment of tumours in superficial localisations. Thus far, the underlying mechanisms of PDT regarding cellular responses and gene regulation are poorly understood. Photochemically generated singlet oxygen (102) is mainly responsible for cytotoxicity induced by PDT. If targeted cells are not disintegrated, photo-oxidative stress leads to transcription and translation of various stress response and cytokine genes. Tumour necrosis factor (TNF) a, interleukin (IL) 1 and IL-6 are strongly induced by photodynamic treatment, supporting inflammatory action and immunological anti-tumour responses. To investigate the first steps of gene activation, this study focused on the proto-oncogenes c-jun and c-fos, both coding for the transcription factor activator protein 1 (AP-1), which was found to mediate IL-6 gene expression. We here determine the effects of photodynamic treatment on transcriptional regulation and DNA binding of transcription factor AP-1 in order to understand the modulation of subsequent regulatory steps. Photodynamic treatment of epithelial HeLa cells was performed by incubation with Photofrin and illumination with 630 nm laser light in vitro. Expression of the c-jun and c-fos genes was determined by way of Northern blot analysis, and DNA-binding activity of the transcription factor AP-1 was evaluated by electrophoretic mobility shift assay (EMSA). Photofrin-mediated photosensitisation of HeLa cells resulted in a rapid and dose-dependent induction of both genes but preferential expression of c-jun. Compared with the transient expression of c-jun and c-fos by phorbol ester stimulation, photodynamic treatment led to a prolonged activation pattern of both immediate early genes. Furthermore, mRNA stability studies revealed an increased half-life of c-jun and c-fos transcripts resulting from photosensitisation. Although mRNA accumulation after PDT was stronger and more prolonged compared with phorbol ester stimulation, with regard to AP-1 DNA-binding activity, phorbol ester was more efficient. Surprisingly, in addition to the activation of AP-1 DNA-binding via PDT, photodynamic treatment can decrease AP-1 DNA-binding of other strong inducers, such as the protein kinase C-mediated pathway of phorbol esters and the antioxidant pyrrolidine dithiocarbamate (PDTC). This study demonstrates a strong induction of c-jun and c-fos expression by PDT, with prolonged kinetics and mRNA stabilisation as compared with activation by phorbol esters. Interestingly, this observation is not coincident with an overinduction of AP-1 DNA-binding, hence suggesting that post-translational modifications are dominant regulatory mechanisms after PDT that tightly control AP-1 activity in the nucleus thus limiting the risk of deregulated oncogene expression.

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“…The fragment of human c-fos gene was isolated from c-fos pSPT18/19 [15] and mRNA destabilizing sequence [16,17] in its 3' non-coding region was removed before insertion.…”

Section: Dna Constructionmentioning

confidence: 99%

Expression of c‐fos gene inhibits proteoglycan synthesis in transfected chondrocyte

et al. 1996

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Removal of a 67-base-pair sequence in the noncoding region of protooncogene fos converts it to a transforming gene.

Cited by 190 publications

References 26 publications

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c-fos mRNAs interact with the same cellular factors

Strong and prolonged induction of c-jun and c-fos proto-oncogenes by photodynamic therapy

Expression of c‐fos gene inhibits proteoglycan synthesis in transfected chondrocyte

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