The Regulatory Network between TTP, MKP-1 and MAPK Signaling in Adipogenesis
Date Issued
2009
Date
2009
Author(s)
Lin, Nien-Yi
Abstract
Dysregulation of adipogenesis has been considered as a cause of the development of obesity and obesity-related diseases. Among the immediate early genes (IEGs) activated during the differentiation of 3T3-L1 preadipocytes, we identified tristetraprolin (TTP), a zinc finger-containing RNA-binding protein which was reported to bind AU-rich elements (AREs) of target mRNAs and induce their rapid degradation. To understand how TTP may be involved in regulating adipogenesis, the expression and mRNA targets of TTP were analyzed. Biochemical and functional assays showed that the expression of TTP per se was autoregulated. Sequence analysis of 3’UTR of IEG mRNAs differentially bound by TTP suggested a preferential binding sequence of UUAUUUAUU. In addition to TTP and the previously reported COX-2 mRNAs, we have also identified MKP-1 mRNA as a novel target of TTP. The expression of MKP-1 and TTP was simultaneously activated by ERK signaling, while MKP-1 protein functions as a feedback regulator of ERK. Moreover, the expression of MKP-1 was tightly controlled by ARE-binding proteins TTP and HuR. Binding of TTP to MKP-1 mRNA resulted in rapid decay and binding of HuR resulted in mRNA stabilization. The three AREs in MKP-1 3’UTR were differentially bound by TTP and HuR. More specifically, both of TTP and HuR preferentially bound to MKP-1 ARE1 and ARE2, but showed low binding affinity to MKP-1 ARE3. The RNA-binding affinity of TTP was posttranslationally modified by p38 and ERK signaling. TTP exhibited a decreased RNA binding while being phosphorylated by p38 signaling and showed an enhanced RNA binding while being phosphorylated by ERK signaling. The functional importance of TTP and MKP-1 during 3T3-L1 differentiation was further demonstrated by siRNA knockdown experiment. These results suggested that TTP can regulate the MKP-1 mRNA stability to subsequently control the activation of MAPK signaling pathways in adipocyte differentiation.
Subjects
adipogenesis
ARE
posttranscriptional regulation
posttranslational modification
SDGs
Type
thesis
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