Tristetraprolin: Roles in cancer and senescence

Cancer and senescence are both complex transformative processes that dramatically alter many features of cell physiology and their interactions with surrounding tissues. Developing the wide range of cellular features characteristic of these conditions requires profound alterations in global gene expression patterns, which can be achieved by suppressing, activating, or uncoupling cellular gene regulatory pathways. Many genes associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA-destabilizing elements (AREs) located in their 3′-untranslated regions. As such, cellular factors that recognize and control the decay of ARE-containing mRNAs can influence tumorigenic or senescent phenotypes mediated by products of these transcripts. In this review, we discuss evidence showing how suppressed expression and/or activity of the ARE-binding protein tristetraprolin (TTP) can contribute to these processes. Next, we outline current findings linking TTP suppression to exacerbation of individual tumorigenic phenotypes, and the roles of specific TTP substrate mRNAs in mediating these effects. Finally, we survey potential mechanisms that cells may employ to suppress TTP expression in cancer, and propose potential diagnostic and therapeutic strategies that may exploit the relationship between TTP expression and tumor progression or senescence.

► Tristetraprolin (TTP) binds mRNAs containing AU-rich elements (AREs) and targets them for rapid mRNA decay. ► TTP expression and/or activity are potently downregulated in many human cancers, particularly advanced and aggressive cancers. ► TTP suppresses the expression of many mRNAs encoding factors that control diverse aspects of tumor development and senescence; as such, loss of TTP in cancer reprograms a gene regulatory network that exacerbates many tumorigenic phenotypes.