The Biosynthesis Characteristics of TTP and TNF Can Be Regulated through a Posttranscriptional Molecular Loop

Abstract

The abundant expression of tumor necrosis factor (TNF) is a hallmark of chronic inflammation of the gastrointestinal tract. Prolonged inflammation can lead to inflammatory bowel disease. TNF biosynthesis is regulated both at transcription and posttranscriptional levels. However, the stimulation-induced increase in translation rate is much larger. This might indicate the possibility of a posttranscriptional regulatory mechanism. How, during basal conditions, is the free concentration of TNF tightly regulated at low levels? The stability and translational efficiency of TNF transcript are regulated by an AU-rich element (ARE) in the 3-UTR of messenger RNA. A transacting protein, TTP, binds to ARE and enhances the mRNA turnover. Here, we examine a proposal that TNF homeostasis is regulated by a TTP-TNF interaction loop at the posttranscriptional level. We propose a computational framework of this regulatory loop by modeling the role of AREs in mediating the messenger RNA stability and translation. This posttranscriptional regulatory loop between TTP and TNF is composed of two feedback loops (i.e. positive and negative). The mutual interaction of these feedback loops regulates the biosynthesis response of TNF during basal and inflammatory conditions. Here, we also propose an explanation for why the p38 inhibitors become insensitive for TTP knock-out mice.

Expression of the mRNA stability regulator Tristetraprolin is required for lactation maintenance in the mouse mammary gland

“…To our knowledge, there is no evidence that TTP directly represses transcription of inflammatory cytokines, but a molecular model for understanding regulation of TNFα biosynthesis through two Post-transcriptional loops has been proposed. One loop is based on the positive feed-back generated by TNFα itself mediating expression of its own transcript, while the negative feedback would be due to TTP-mediated degradation of TNF α mRNA and TNFα-mediated expression of Ttp transcript [ 4 , 41 ]. In addition, TTP might be repressing the initiation of inflammatory pathways acting together with glucocorticoids.…”

Negative Feed-forward Control of Tumor Necrosis Factor (TNF) by Tristetraprolin (ZFP36) Is Limited by the Mitogen-activated Protein Kinase Phosphatase, Dual-specificity Phosphatase 1 (DUSP1)

“…However, whereas the regulation of signal transduction and gene expression involves a myriad of signaling molecules leading to transcriptional, post-transcriptional, translational, and often post-translational control of gene expression, it is routine to depict these assemblies as simple linear pathways. Using TNF biosynthesis as an example, regulation involves the integrated effect of feedback and feed-forward control loops (2,41). The current study documents interplay between the phosphatase, DUSP1, and the mRNA-destabilizing protein, ZFP36, in the regulation of TNF mRNA as a model ARE-containing transcript.…”

“…However, increased TNF expression is also associated with the pathogenesis of chronic inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, and asthma (1). Indeed, TNF expression is tightly regulated at a molecular level by transcriptional and post-transcriptional mechanisms (2). Whereas transcriptional control involves recruitment of factors, such as nuclear factor (NF)-B, to the TNF promoter, post-transcriptional regulation is conferred via multiple copies of the adenylate-uridylate-rich element (ARE) 2 (3), AUUUA, located in the 3Ј-UTR of the TNF mRNA (4).…”

“…Indeed, TNF expression is tightly regulated at a molecular level by transcriptional and post-transcriptional mechanisms (2). Whereas transcriptional control involves recruitment of factors, such as nuclear factor (NF)-B, to the TNF promoter, post-transcriptional regulation is conferred via multiple copies of the adenylate-uridylate-rich element (ARE) 2 (3), AUUUA, located in the 3Ј-UTR of the TNF mRNA (4). Such regions are critical for regulating message stability and are targeted by several RNA-binding proteins, including tristetraprolin (also known as zinc finger protein 36 (ZFP36)), human antigen R (HuR or ELAVL1), adenine-uridine-rich element RNA-binding factor-1 (AUF1 or HNRNPD), and K-homology domain splicing regulatory protein (KHSRP) (5)(6)(7)(8)(9).…”

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease

“…As such, the RBP TTP is protective in inflammatory conditions involving diabetes and atherosclerosis by acting as a mediator for pro-inflammatory cytokine degradation [ 79 ]. For example, in the case of increased expression of tumor necrosis factor (TNF), a hallmark indicator of chronic inflammation, TNF homeostasis is regulated by TTP and, more specifically, by a post transcriptional regulatory positive or negative feedback loop [ 80 ]. An additional illustration of a prospective treatment strategy on the subject of heart disease is Poly(C)-binding protein 2 (PCBP2) which was shown to be reduced in the diseased heart in humans as well as in hypertrophied hearts in mice.…”