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Ultraviolet Light-Induced Regulation of Transcription and Translation, COX-2 Expression and Noncanonical NF-κB Activation

Carpenter, Oliver L.
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1382624015

Abstract Details

2013, Doctor of Philosophy (PhD), Ohio University, Chemistry and Biochemistry (Arts and Sciences).
NF-κB is a transcription factor that controls expression of genes involved in the immune and inflammatory responses as well a being a key component in the onset of cancers. In this study we provided evidence that MSK1 is responsible for a non-canonical late-phase activation of NF-κB upon UVB irradiation. Our data demonstrated that following UV irradiation, MSK1 is activated via phosphorylation at the 24 h time point coinciding with translocation of NF-κB into the nucleus. Investigations into the signaling pathways upstream of MSK1 through the use of specific inhibitors for mitogen-activated protein kinase and p38 revealed that both kinases are required for full phosphorylation during the late-phase (24 h), while p38 is paramount for phosphorylation during the early-phase (6 h). Electromobilty shift assays (EMSA) showed that inhibition of MSK1 resulted in a marked reduction in NF-κB binding affinity without altering the nuclear translocation of NF-κB. Supershift EMSA implicate that the p65, but not p50, isoform of NF-κB is involved in late-phase activation in response to UVB irradiation. Together, the results of these studies shed light onto a novel pathway of MSK1 mediated late-phase activation of NF-κB in response to UV irradiation. Exposure to UV induces a prolonged expression of COX-2 via transcriptional activation that is due in part to an increase in NF-κB activity. While transcriptional regulation of COX-2 expression has been well studied, the role of translational regulation of COX-2 synthesis upon UV-irradiation is not yet clear. In this study, we show that the phosphorylation of the alpha subunit of eIF2α plays an important role in the regulation of COX-2 expression after UV-irradiation. Our data demonstrates that UV light induces COX-2 expression in wild-type mouse embryo fibroblasts (MEFS/S) and that the inducibility is reduced in MEFA/A cells in which the phosphorylation site, Ser-51 in eIF2α, is replaced with a nonphosphorylatable Ala (S51A). UV light-induced transcription of COX-2 is delayed in MEFA/A cells, which correlates with NF-κB activation as we previously reported (Wu et. Al, J. Bio. Chem, 2004). Additionally, the translational regulation of COX-2 binding protein TIAR expression is reduced in MEFS/S cells but not in MEFA/A cells at 24 hours post-UV. These results suggest that translation initiation plays a role in a complex and dynamic regulation of COX-2 expression. Based on our results we proposed a novel eIF2α phosphorylation-centered network for the regulation of COX-2 expression after UV irradiation.
Shiyong Wu, PhD (Advisor)
115 p.
Biochemistry; Cellular Biology; Molecular Biology; Oncology
Nuclear Factor Kappa B; NF-kB; COX2; MSK1; Ultraviolet; UV; Ultraviolet light; Mitogen and Stress Activated; NF-kB regulation; Nuclear Factor Kappa B regulation; MAPK; MSK1 regulation; UV Light; ROS; Translation and Transcription Regulation

Recommended Citations

Citations

  • Carpenter, O. L. (2013). Ultraviolet Light-Induced Regulation of Transcription and Translation, COX-2 Expression and Noncanonical NF-κB Activation [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1382624015

    APA Style (7th edition)

  • Carpenter, Oliver. Ultraviolet Light-Induced Regulation of Transcription and Translation, COX-2 Expression and Noncanonical NF-κB Activation. 2013. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1382624015.

    MLA Style (8th edition)

  • Carpenter, Oliver. "Ultraviolet Light-Induced Regulation of Transcription and Translation, COX-2 Expression and Noncanonical NF-κB Activation." Doctoral dissertation, Ohio University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1382624015

    Chicago Manual of Style (17th edition)

ohiou1382624015
310
© 2013, all rights reserved.
This open access ETD is published by Ohio University and OhioLINK.