Rapamycin destabilizes interleukin-3 mRNA in autocrine tumor cells by a mechanism requiring an intact 3' untranslated region.

Abstract

We analyzed the effect of rapamycin on autocrine mast cell tumor lines with abnormally stable interleukin-3 (IL-3) transcripts due to a defect in mRNA degradation. Rapamycin inhibited IL-3 mRNA expression specifically, while transcripts of IL-4 and IL-6 were not affected. As indicated by the use of the transcriptional inhibitor actinomycin D or by reporter constructs, inhibition was posttranscriptional and resulted from destabilization of the mRNA. Transcripts from transgenes lacking the AU-rich 3' untranslated region were refractory to drug-induced degradation, suggesting that these 3' sequences contain the target of the rapamycin effect. Rapamycin did not promote IL-3 mRNA degradation in cells of a tumor variant lacking expression of FKBP12, the binding protein of rapamycin. Experiments with wortmannin indicated that rapamycin does not act via p70S6 kinase. FK-506, another ligand of FKBP12 affecting the phosphatase calcineurin, did not antagonize but shared the effect of rapamycin. Our data fit a model whereby both FKBP12 and calcineurin target an unknown regulator of IL-3 mRNA turnover.

• Authors: R Banholzer, A P Nair, H H Hirsch, X F Ming, C Moroni
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 17 Issue 6 Pg. 3254-60 (Jun 1997) ISSN: 0270-7306 [Print] United States
• PMID: 9154824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Carrier Proteins
• DNA-Binding Proteins
• Heat-Shock Proteins
• Immunosuppressive Agents
• Interleukin-3
• Polyenes
• RNA, Messenger
• Cyclosporine
• Protein Serine-Threonine Kinases
• Ribosomal Protein S6 Kinases
• Amino Acid Isomerases
• Tacrolimus Binding Proteins
• Sirolimus
• Tacrolimus

Topics

• Amino Acid Isomerases (metabolism)
• Animals
• Antibiotics, Antineoplastic (metabolism, pharmacology)
• Binding Sites
• Carrier Proteins (metabolism)
• Cell Division (drug effects)
• Cyclosporine (pharmacology)
• DNA-Binding Proteins (metabolism)
• Down-Regulation (drug effects)
• Heat-Shock Proteins (metabolism)
• Immunosuppressive Agents (pharmacology)
• Interleukin-3 (genetics)
• Mice
• Polyenes (metabolism, pharmacology)
• Protein Processing, Post-Translational
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• RNA, Messenger (metabolism)
• Ribosomal Protein S6 Kinases
• Sirolimus
• Tacrolimus (pharmacology)
• Tacrolimus Binding Proteins
• Tumor Cells, Cultured