Regulation of mRNA Stability in Chemokine Gene ExpressionAuthor InfoSocial Media
2008, Doctor of Philosophy, Case Western Reserve University, Pathology.
Proper expression of pro-inflammatory genes, including ELR+ CXC chemokines, is achieved through regulation of transcription and post-transcriptional processes including mRNA decay. Modulation of transcription is an important means of achieving stimulus-induced expression and the mechanisms of this response have been well-characterized. mRNA stability is becoming increasingly recognized as a critical factor influencing expression of these genes. The mRNAs are constitutively unstable, but are stabilized in response to a variety of stimuli to allow robust expression.
IL-17-induced gene expression has emerged as a critical factor driving inflammation in both host defense and autoimmunity. However, the molecular mechanisms by which IL-17 regulates expression are poorly understood. IL-17 alone has little effect on gene expression, but induces a synergistic response in combination with TNFα. We have determined that this observation is explained by the finding that IL-17 has relatively little effect on transcription, but rather works primarily through mRNA stabilization. It thus cooperates with TNFα, which drives transcription but is unable to prolong mRNA half-life, by providing a distinct requirement for gene expression. Although the adaptors Act1 and TRAF6 have both been previously reported to be essential for IL-17-induced responses, we find that only Act1 is involved in mRNA stabilization. Taken together our finds indicate the existence of a novel signaling pathway downstream of Act1 that is responsible for mRNA stabilization and plays a central role in IL-17-induced gene expression.
The finding that IL-17-induced stabilization does not require TRAF6 raised questions regarding the role of this adaptor in IL-1α-induced mRNA stabilization. Although all IL-1α driven responses previously examined, including NF-κB and MAP kinase activation, require TRAF6, surprisingly we have found that TRAF6 is not required for IL-1α-induced mRNA stabilization. The signals leading to these earlier examined endpoints and mRNA stabilization diverge at IRAK1, the molecule immediately upstream of TRAF6 in the pathway. Collectively, these findings further highlight the importance of the regulation of mRNA stability in pro-inflammatory gene expression and provide understanding of the receptor proximal signaling events that allow IL-17 and IL-1α to link to this endpoint.
Thomas Hamilton, PhD (Advisor)
Clifford Harding, MD/PhD (Committee Chair)
Ganes Sen, PhD (Committee Member)
George Dubyak, PhD (Committee Member)
Clive Hamlin, PhD (Committee Member)
TRAF6; IL-17; MRNA; mRNA Stabilization; IRAK1; Act1; TNF
Hartupee, J. (2008). Regulation of mRNA Stability in Chemokine Gene Expression. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/
Hartupee, Justin. "Regulation of mRNA Stability in Chemokine Gene Expression." Electronic Thesis or Dissertation. Case Western Reserve University, 2008. OhioLINK Electronic Theses and Dissertations Center. 12 Mar 2014.
Hartupee, Justin C. "Regulation of mRNA Stability in Chemokine Gene Expression." Electronic Thesis or Dissertation. Case Western Reserve University, 2008. https://etd.ohiolink.edu/