A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA.
The occurrence of pathologically stable mRNAs of proto-oncogenes, growth factors and cyclins has been proposed to contribute to experimental and human oncogenesis. In normal resting cells, mRNAs containing an AU-rich element (ARE) in their 3' untranslated region are subjected to rapid degradation. Tristetraprolin (TTP) is an RNA-binding zinc-finger protein that promotes decay of ARE-containing mRNAs. Here we report that TTP acts as a potent tumor suppressor in a v-H-ras-dependent mast cell tumor model, where tumors express abnormally stable interleukin-3 (IL-3) mRNA as part of an oncogenic autocrine loop. Premalignant v-H-ras cells were transfected with TTP and injected into syngeneic mice. TTP expression delayed tumor progression by 4 weeks, and late appearing tumors escaped suppression by loss of TTP. When transfected into a fully established tumor line, TTP reduced cloning efficiency in vitro and growth of the inoculated cells in vivo. Transgenic TTP interfered with the autocrine loop by enhancing the degradation of IL-3 mRNA with concomitant reduction of IL-3 secretion. Our data establish the ARE as an antioncogenic target in a model situation, underline the importance of mRNA stabilization in oncogenesis and show for the first time that tumor suppression can be achieved by interfering with mRNA turnover.
Stoecklin
Georg
G
Institute of Medical Microbiology, University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
Gross
Brigitte
B
Ming
Xiu-Fen
XF
Moroni
Christoph
C
D020413:3' Untranslated Regions; D000241:Adenosine / Q000235:genetics; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D001665:Binding Sites; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005260:Female; D016147:Genes, Tumor Suppressor; D016313:Genes, abl; D011905:Genes, ras; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007377:Interleukin-3 / Q000235:genetics* / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009154:Mutation; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051816:Tristetraprolin; D014407:Tumor Cells, Cultured; D014529:Uridine / Q000235:genetics; D016335:Zinc Fingers
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007377:Interleukin-3; D012333:RNA, Messenger; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; D000241:Adenosine; D014529:Uridine