The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

Abstract

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

Tristetraprolin Posttranscriptionally Downregulates TRAIL Death Receptors

“…Similarly, cytoplasmic DR4/5 was revealed to induce cell death in response to unresolved ER stress [ 31 , 32 ]. With regard to TTP in this specific function of noncanonical location of DRs, at what stage occur remains unknown, TTP may also act on DRs mRNA that are involved in these pathways because TTP regulate mRNA targets at various stages during carcinogenesis and modulate tumor cell apoptosis by directly regulating the apoptotic mediators within both intrinsic and extrinsic pathways [ 33 ].…”

Tristetraprolin prevents gastric metaplasia in mice by suppressing pathogenic inflammation

“…Zfp36 encodes a zinc finger RNA binding protein, TTP, that binds to ARE-containing mRNAs and destabilizes them by recruiting deadenylases, thus promoting mRNA decay (35). It has been estimated that about 26% of human mRNA 3'UTRs contain at least a single minimal TTP family binding site, UAUUUAU or UAUUUUAU (36), and disruption of TTP family members has been associated with inflammatory disorders and cancer (15,(37)(38)(39). TTP is a critical regulator of numerous proinflammatory cytokines.…”

“…TTP is a critical regulator of numerous proinflammatory cytokines. TTP KO mice develop multi-system inflammatory disease that is largely due to excessive TNF expression (15,17,40). In contrast, increased TTP expression confers resistance to numerous inflammatory pathologies including arthritis and dermatitis (20)(21)(22).…”

“…The ideal binding sequence, UUAUUUAUU or its variants, recognized by TTP, is found in a host of transcripts that encode pro-inflammatory cytokines, chemokines and oncogenes (14,15). Loss of TTP expression increases the half-life of target mRNAs, and TTP expression is reduced or lost in numerous cancers, including gastric cancer (15,16). Germline Zfp36 KO mice exhibit numerous systemic inflammatory pathologies such as dermatitis, arthritis, autoimmunity, and myeloid hyperplasia, all of which are linked to aberrant expression of the proinflammatory cytokine TNF (17).…”

“…TTP binding initiates de-adenylation and degradation of the target transcript (13). The ideal binding sequence, UUAUUUAUU or its variants, recognized by TTP, is found in a host of transcripts that encode pro-inflammatory cytokines, chemokines and oncogenes (14,15). Loss of TTP expression increases the half-life of target mRNAs, and TTP expression is reduced or lost in numerous cancers, including gastric cancer (15,16).…”