Post-transcriptional regulation of tumour necrosis factor alpha production

Abstract

The 3' untranslated region of mRNAs encoding short lived immediate early genes (for example, fos, jun) as well as selected cytokines (for example, TNFα, GM-CSF) possess AU-rich elements that regulate protein expression. Class I AREs consist of one or more pentamer repeats (that is, AUUUA), whereas class II AREs consist of one or more nonamer repeats (that is, AUUUAUUUA). Whereas class I AREs are sufficient to promote the degradation of transcripts encoding immediate early proteins, both class I and class II AREs regulate the production of cytokines such as TNFα, GM-CSF, interleukin 3 (IL3) and interferon α (IFNα). The 3' untranslated region of TNFα transcripts contains both class I and class II AREs. Electrophoretic mobility shift assays have identified two distinct regulatory complexes that assemble on these adjacent cis elements in HeLa cells.14 15 The complex assembled on the class II ARE (designated complex 1) includes the related RNA binding proteins TIA-1 and TIAR.14 The complex assembled on the class I ARE (designated complex 2) includes an unidentified 55 kDa protein. Whereas complex 1 forms with extracts derived from activated and unactivated macrophages, complex 2 is only formed using extracts derived from activated macrophages.