Induction of Rapid IL-β mRNA Degradation in THP-1 Cells Mediated Through the AU-Rich Region in the 3′UTR by a Radicicol Analogue

Kastelic, Tania; Schnyder, Jög; Leutwiler, Albert; Traber, René; Streit, Bruno; Niggli, Heinz; MacKenzie, Andrew; Cheneval, Dominique

doi:10.1006/cyto.1996.0100

Cited by 51 publications

(35 citation statements)

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“…Supporting this rationale is the observation by others that activation of p38 can be blocked by inhibiting Hsp90 (11,13,18). Activated p38 is implicated in maintaining messenger RNA (mRNA) stability through its actions on 3Ј AU-rich elements involved in transcriptional stability (9,11). The effect of JNK signaling knockdown, as shown here, on mRNA stability is less clear.…”

Section: Small Molecule Inhibitors Of Hsp90 In Inflammatory Diseasementioning

confidence: 73%

“…Aberrant cytokine and receptor signaling, angiogenesis, and cellular invasion are common to both cancer and inflammation. Natural product inhibitors of Hsp90 block activation of the NF-B pathway, leading to loss of cytokine production in macrophages and other cell types (9)(10)(11)(12)(13). Receptor-interacting protein (RIP) and IKK, members of the NF-B signaling pathway, have been shown to be Hsp90 clients that are degraded following Hsp90 inhibition (14)(15)(16)(17).…”

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confidence: 99%

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Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

Rice¹,

Veal²,

Fadden³

et al. 2008

Arthritis & Rheumatism

125

111

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Objective. To evaluate the ability of SNX-7081, a novel small molecule inhibitor of Hsp90, to block components of inflammation, including cytokine production, protein kinase activity, and angiogenic signaling. A close analog was evaluated in preclinical in vivo models of rheumatoid arthritis (RA).Methods. SNX-7081 binding to Hsp90 was characterized in Jurkat cells and RA synovial fibroblasts (RASFs). Inhibition of NF-B nuclear translocation was evaluated in cellular systems, using lipopolysaccharide (LPS), tumor necrosis factor ␣, or interleukin-1␤ stimulation. Suppression of cytokine production in THP-1 cells, human umbilical vein endothelial cells, and RASFs was studied. Disruption of MAPK signaling cascades by SNX-7081 following growth factor stimulation was assessed. SNX-7081 was tested in 2 relevant angiogenesis assays: platelet-derived growth factor activation of fibroblasts and LPS-induced nitric oxide (NO) release in J774 macrophages. A close analog, SNX-4414, was evaluated in rat collagen-induced arthritis and adjuvant-induced arthritis, following oral treatment.Results. SNX-7081 showed strong binding affinity to Hsp90 and expected induction of Hsp70. NF-B nuclear translocation was blocked by SNX-7081 at nanomolar concentrations, and cytokine production was potently inhibited. Growth factor activation of ERK and JNK signaling was significantly reduced by SNX-7081. NO production was also sharply inhibited. In animal models, SNX-4414 fully inhibited paw swelling and improved body weight. Scores for inflammation, pannus formation, cartilage damage, and bone resorption returned to normal.Conclusion. The present results demonstrate that a small molecule Hsp90 inhibitor can impact inflammatory disease processes. The strong in vivo efficacy observed with SNX-4414 provides preclinical validation for consideration of Hsp90 inhibitors in the treatment of RA.

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Section: Small Molecule Inhibitors Of Hsp90 In Inflammatory Diseasementioning

confidence: 73%

mentioning

confidence: 99%

Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

Rice¹,

Veal²,

Fadden³

et al. 2008

Arthritis & Rheumatism

125

111

View full text Add to dashboard Cite

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“…These AREs contain clusters of AUUUA pentamer repeats, which are well-known instability determinants for mRNAs. They are often present in the 3 -UTRs of short-lived, rapidly regulated mRNAs, such as the mRNAs for the cytokines IL-1 (Kastelic et al 1996), IL-2 (Henics et al 1994) and IL-3 (Mayo et al 1995), granulocyte-macrophage colonystimulating factor (GM-CSF) (Esnault et al 1998), tumor necrosis factor-(TNF-) (Wang et al 1997), and for the early genes c-fos (Chagnovich & Cohn 1997), c-jun (Peng et al 1996) and c-myc (Chagnovich & Cohn 1997). The AREs have been shown to be responsible for the short half-lives of these transcripts.…”

Section: Discussionmentioning

confidence: 99%

“…The 1·5 kb cyclin D1 mRNA only has about 200 residues in its 3 -UTR and lacks the AUUUA repeats. The AUUUA sequences are known as instability determinants (Ross 1995), and are present in many rapidly regulated transcripts (Henics et al 1994, Mayo et al 1995, Kastelic et al 1996, Peng et al 1996, Chagnovich & Cohn 1997, Wang et al 1997, Esnault et al 1998. To determine whether other transcripts, containing AUUUA repeats in their 3 -UTR, are influenced by PI3-K in the same way, we studied the effect of LY294002 on c-fos, c-jun and c-myc mRNA stability in MCF-7 cells.…”

Section: Stabilization Of Mrna By Pi3-k Is Specific For Cyclin D1mentioning

confidence: 99%

Stabilization of cyclin D1 mRNA via the phosphatidylinositol 3-kinase pathway in MCF-7 human breast cancer cells

Dufourny

Teeffelen²,

Hamelers³

et al. 2000

Journal of Endocrinology

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Treatment of quiescent MCF-7 human breast cancer cells with either the polypeptide growth factors insulin-like growth factor-I (IGF-I) or epidermal growth factor (EGF), the steroid hormone estradiol (E2) or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) results in increased steady-state levels of cyclin D1 mRNA and protein. Unexpectedly, this elevation of cyclin D1 expression by all of these agents is inhibited by the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. Since transcriptional activation of the cyclin D1 promoter by EGF, E2 and TPA is independent of PI3-K activity, these findings suggest a post-transcriptional role for PI3-K in the regulation of cyclin D1 expression. Here we show that inhibition of PI3-K by LY294002 decreases the half-life of the 4·5 kb cyclin D1 mRNA species. In contrast, the stability of the 1·5 kb cyclin D1 mRNA is not affected by PI3-K inhibition. PI3-Kmediated stabilization of mRNA is not a general phenomenon, since other rapidly regulated and unstable mRNAs, such as those encoding c-fos, c-jun and c-myc, are not stabilized upon activation of the PI3-K signaling pathway.

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“…It has been shown that certain AREs act as instability determinants (Lagnado et al 1994;Chen and Shyu 1995). For instance, the stable ␤-globin mRNA was rendered unstable when its 3Ј untranslated region (UTR) was replaced with the GMCSF multiple ARE 3Ј UTR (Shaw and Kamen 1986), whereas the unstable interleukin-1␤ mRNA was rendered stable when AREs were removed (Kastelic et al 1996). Despite the accumulating evidence of the functional role of AREs in mRNA stability, the repertoire of the ARE genes and their regulatory pathways remains largely unknown.…”

mentioning

confidence: 99%

An Integrated Computational and Laboratory Approach for Selective Amplification of mRNAs Containing the Adenylate Uridylate-Rich Element Consensus Sequence

Khabar

Dhalla²,

Bakheet³

et al. 2002

Genome Res.

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Messenger RNAs that have the stability determinants, adenylate uridylate-rich elements (AREs), in their 3Ј untranslated region (UTR) code for key products that regulate early and transient biological responses. We used a computational laboratory approach for amplification of large, including full-length, protein-coding regions for ARE genes. Statistical analysis of the initiation regions in the 5Ј UTR of ARE-mRNAs was performed. Accordingly, several 5Ј primers and a single universal 3Ј primer that targeted the initiation consensuses and ARE regions, respectively, were designed. Using optimized conditions, the primers were able to enrich and amplify large protein-coding regions for the ARE gene family. The selective amplification of ARE cDNAs was verified using specific polymerase chain reactions (PCRs) to known ARE mRNA molecules and monitoring the abundance of the non-ARE ␤-actin signal. A mini-library from the amplified ARE products was constructed for further confirmation of ARE selection. Distinct ARE amplified cDNA pools were selectively generated by distinct 5Ј primers. The biological utility of the method was shown with differential display. The up-regulation of several ARE-mRNAs, including the full-length coding region of the small inducible cytokine A4 (SCYA4) gene, was shown in endotoxin-stimulated monocytic cells. The integrated computational and laboratory approach should lead to enhanced capability for discovery and expression analysis of early and transient response genes.

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Induction of Rapid IL-β mRNA Degradation in THP-1 Cells Mediated Through the AU-Rich Region in the 3′UTR by a Radicicol Analogue

Cited by 51 publications

References 0 publications

Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

Stabilization of cyclin D1 mRNA via the phosphatidylinositol 3-kinase pathway in MCF-7 human breast cancer cells

An Integrated Computational and Laboratory Approach for Selective Amplification of mRNAs Containing the Adenylate Uridylate-Rich Element Consensus Sequence

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