Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines.
ABSTRACT The tristetraprolin (TTP) family of tandem zinc finger proteins comprises three members in man and most other mammals, with a fourth expressed in rodents. In mice, gene disruption of TTP itself leads to a systemic inflammatory syndrome that is mediated in large part by over-expression of tumor necrosis factor alpha (TNF). This increased expression is secondary to stabilization of the TNF mRNA in the TTP KO mice, a finding that led to the characterization of TTP as an mRNA binding protein that can promote the removal of the poly(A) tail from selected mRNAs and facilitate their nucleolytic destruction. The other human family members behave similarly to TTP in over-expression studies of transfected cells, but gene disruption experiments have implicated them in different physiological processes. In the present study, we developed a real-time PCR assay for all three human family members that allowed for comparative measurements of all three family members in the same tissues and cells. We used this assay to quantitate expression levels of all three transcripts in a variety of normal human tissues, as well as in the ;;NCI 60", a well characterized panel of human tumor cell lines. Although studies in fibroblasts and macrophages derived from knockout mice have failed to demonstrate compensatory expression of the family members in terms of transcript levels, it remains possible that the different family members can function as ;;TTP equivalents" in certain physiological or pathological circumstances.
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ABSTRACT: Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is one of several Zinc Finger Protein 36 (Zfp36) family members, which bind AU rich elements within 3' untranslated regions (UTRs) to negatively regulate the post-transcriptional expression of targeted mRNAs. The prototypical member of the family, Tristetraprolin (TTP or ZFP36), has been well-studied in the context of inflammation and plays an important role in repressing pro-inflammatory transcripts such as TNF-α. Much less is known about the other family members, and none have been studied in the context of infection. Using macrophage cell lines and primary alveolar macrophages we demonstrated that, like ZFP36, ZFP36L1 is prominently induced by infection. To test our hypothesis that macrophage production of ZFP36L1 is necessary for regulation of the inflammatory response of the lung during pneumonia, we generated mice with a myeloid-specific deficiency of ZFP36L1. Surprisingly, we found that myeloid deficiency of ZFP36L1 did not result in alteration of lung cytokine production after infection, altered clearance of bacteria, or increased inflammatory lung injury. Although alveolar macrophages are critical components of the innate defense against respiratory pathogens, we concluded that myeloid ZFP36L1 is not essential for appropriate responses to bacteria in the lungs. Based on studies conducted with myeloid-deficient ZFP36 mice, our data indicate that, of the Zfp36 family, ZFP36 is the predominant negative regulator of cytokine expression in macrophages. In conclusion, these results imply that myeloid ZFP36 may fully compensate for loss of ZFP36L1 or that Zfp36l1-dependent mRNA expression does not play an integral role in the host defense against bacterial pneumonia.PLoS ONE 10/2014; 9(10):e109072. DOI:10.1371/journal.pone.0109072 · 3.53 Impact Factor
Article: Stress granules, P-bodies and cancer[Show abstract] [Hide abstract]
ABSTRACT: Cancer cells are exposed to adverse conditions in the tumor microenvironment, and utilize post-transcriptional control mechanisms to re-program gene expression in ways that enhance cell survival. Stress granules and processing bodies are RNA-containing granules that contribute to this process by modulating cellular signaling pathways, metabolic machinery, and stress response programs. This review examines evidence implicating RNA granules in the pathogenesis of cancer and discusses their potential as targets for anticancer therapies. This article is part of a Special Issue entitled: Translation and Cancer. Copyright © 2014. Published by Elsevier B.V.Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 12/2014; DOI:10.1016/j.bbagrm.2014.11.009 · 5.44 Impact Factor
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ABSTRACT: Cysteine3Histidine (CCCH)-type zinc finger proteins comprise a large family that is well conserved across eukaryotes. Among them, tandem CCCH zinc finger proteins (TZFs) play critical roles in mRNA metabolism in animals and yeast. While there are only three TZF members in humans, a much higher number of TZFs has been found in many plant species. Notably, plant TZFs are over-represented by a class of proteins containing a unique TZF domain preceded by an arginine (R)-rich (RR) motif, hereafter called RR-TZF. Recently, there has been a large number of reports indicate that RR-TZF proteins can localize to Processing-bodies (P-bodies) and stress granules (SG), two novel cytoplasmic aggregations of messenger ribonucleoprotein complexes (mRNPs), and play critical roles in plant growth, development, and stress response, likely via RNA regulation. This review focuses on the classification and most recent development of molecular, cellular, and genetic analyses of plant RR-TZF proteins.Plant and Cell Physiology 05/2014; DOI:10.1093/pcp/pcu074 · 4.98 Impact Factor