Tristetraprolin: A cytosolic regulator of mRNA turnover moonlighting as transcriptional corepressor of gene expression.

Tristetraprolin (TTP) is a nucleocytoplasmic 326 amino acid protein whose sequence is characterized by possessing two CCCH-type zinc finger domains. In the cytoplasm TTP function is to promote the degradation of mRNAs that contain adenylate/uridylate-rich elements (AREs). Mechanistically, TTP promotes the recruitment of poly(A)-specific deadenylases and exoribonucleases. By reducing the half-life of about 10% of all the transcripts in the cell TTP has been shown to participate in multiple cell processes that include regulation of gene expression, cell proliferation, metabolic homeostasis and control of inflammation and immune responses. However, beyond its role in mRNA decay, in the cell nucleus TTP acts as a transcriptional coregulator by interacting with chromatin modifying enzymes. TTP has been shown to repress the transactivation of NF-κB and estrogen receptor suggesting the possibility that it participates in the transcriptional regulation of hundreds of genes in human cells and its possible involvement in breast cancer progression. In this review, we discuss the cytoplasmic and nuclear functions of TTP and the effect of the dysregulation of its protein levels in the development of human diseases. We suggest that TTP be classified as a moonlighting tumor supressor protein that regulates gene expression through two different mechanims; the decay of ARE-mRNAs and a transcriptional coregulatory function.

IFI27/ISG12 Downregulates Estrogen Receptor α Transactivation by Facilitating Its Interaction With CRM1/XPO1 in Breast Cancer Cells.

The estrogen receptor alpha (ERα) is a ligand-activated transcription factor whose activity is modulated by its interaction with multiple protein complexes. In this work, we have identified the protein interferon alpha inducible protein 27 (IFI27/ISG12) as a novel ERα-associated protein. IFI27/ISG12 transcription is regulated by interferon and estradiol and its overexpression is associated to reduced overall survival in ER+ breast cancer patients but its function in mammary gland tissue remains elusive. In this study we showed that overexpression of IFI27/ISG12 in breast cancer cells attenuates ERα transactivation activity and the expression of ERα-dependent genes. Our results demonstrated that IFI27/ISG12 overexpression in MCF-7 cells reduced their proliferation rate in 2-D and 3-D cell culture assays and impaired their ability to migrate in a wound-healing assay. We show that IFI27/ISG12 downregulation of ERα transactivation activity is mediated by its ability to facilitate the interaction between ERα and CRM1/XPO1 that mediates the nuclear export of large macromolecules to the cytoplasm. IFI27/ISG12 overexpression was shown to impair the estradiol-dependent proliferation and tamoxifen-induced apoptosis in breast cancer cells. Our results suggest that IFI27/ISG12 may be an important factor in regulating ERα activity in breast cancer cells by modifying its nuclear versus cytoplasmic protein levels. We propose that IFI27/ISG12 may be a potential target of future strategies to control the growth and proliferation of ERα-positive breast cancer tumors.