The role of tristetraprolin in cancer and inflammation

Abstract

Messenger RNA decay is a critical mechanism to control the expression of many inflammation- and cancer-associated genes. These transcripts are targeted for rapid degradation through AU-rich element (ARE) motifs present in the mRNA 3' untranslated region (3'UTR). Tristetraprolin (TTP) is an RNA-binding protein that plays a significant role in regulating the expression of ARE-containing mRNAs. Through its ability to bind AREs and target the bound mRNA for rapid degradation, TTP can limit the expression of a number of critical genes frequently overexpressed in inflammation and cancer. Regulation of TTP occurs on multiple levels through cellular signaling events to control transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TTP's ability to promote ARE-mediated mRNA decay along with decay-independent functions of TTP. This review summarizes the current understanding of post-transcriptional regulation of ARE-containing gene expression by TTP and discusses its role in maintaining homeostasis and the pathological consequences of losing TTP expression.

Figure 1

Schematic showing the organization of TTP gene, mRNA, and protein. Human TTP gene, ZFP36, consists of two exons and one intron. The arrows represent the genomic location of two SNPs that have been associated with rheumatoid arthritis. ZFP36*2 is located in the promoter, and ZFP36*8 lies in the protein coding region of the second exon. TTP mRNA contains ARE-motifs in the 3’ UTR. TTP protein structure displays unique features including three tetra-proline (PPPP) repeats, two CCCH-type zinc (Zn) finger domains, and several serine/threonine phosphorylation sites.

Figure 2

TTP’s role in ARE-mediated mRNA decay. Processed mRNA transcripts are exported from the nucleus into the cytoplasm wherein the translation initiation complex is assembled. Cytoplasmic TTP associates with these transcripts via ARE binding and further recruits the deadenylase complex. Following deadenylation, the mRNA transcript can undergo 5’- 3’ decay in P-bodies, where the transcript is decapped and the mRNA is stored or decayed by the exonuclease Xrn1. Alternatively, TTP can facilitate 3’- 5’ exosome-mediated decay of target mRNAs. Under conditions of stress, TTP can be recruited to stress granules and may facilitate delivery of translationally-repressed ARE-containing mRNAs from stress granules to P-bodies for degradation.

Figure 3

TTP knockout mouse. Eight-week old TTP knockout mice and wild-type C57Bl/6 are shown. Reduction in weight gain is apparent in the TTP knockout mouse. Symptoms of alopecia and dermatitis can be visualized as patches on skin showing hair loss and mild discoloration, respectively.

Figure 4

TTP-mediated regulation of E6-AP in cervical cancer. A) Immunohistochemistry of TTP expression in normal cervical tissue (left) and HPV-mediated cervical cancer (right). TTP expression (brown staining) is apparent in normal tissue and lost in tumor tissue. B) Binding of TTP to the ARE-containing mRNA of the ubiquitin ligase E6-AP targets it for rapid decay and subsequently counteracts HPV-mediated degradation of p53 tumor suppressor and hTERT transcription leading to cellular senescence.