title: 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.
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas 77030, USA.
authors.forename: Naveed
authors.initials: N
authors.lastname: Aslam
authors.forename: Irum
authors.initials: I
authors.lastname: Zaheer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D003198:Computer Simulation; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006706:Homeostasis; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D020871:RNA Stability; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D012333:RNA, Messenger; C541099:TTP protein, mouse; D014409:Tumor Necrosis Factor-alpha