Dissertation/ Thesis
The Role of MKK3 in Mediating Signals to the p38 MAP Kinase Pathway: A Dissertation
| العنوان: | The Role of MKK3 in Mediating Signals to the p38 MAP Kinase Pathway: A Dissertation |
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| المؤلفون: | Wysk, Mark Allen |
| المساهمون: | Roger J. Davis, Ph.D., Program in Molecular Medicine |
| بيانات النشر: | University of Massachusetts Medical School |
| سنة النشر: | 2022 |
| المجموعة: | University of Massachusetts, Medical School: eScholarship@UMMS |
| مصطلحات موضوعية: | MAP Kinase Signaling System, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Signal Transduction, Amino Acids, Peptides, and Proteins, Cells, Chemical Actions and Uses, Enzymes and Coenzymes |
| الوصف: | Some images did not scan well. Please consult original document. ; p38 mitogen-activated protein (MAP) kinases represent a subgroup of MAP kinases that respond to environmental stress and inflammatory cytokines. p38 MAPK is activated by two upstream kinases, MKK3 and MKK6, by dual phosphorylation on threonine and tyrosine in conserved kinase subdomain VII. Until recently the relative roles of MKK3 and MKK6 have remained unclear. I have undertaken two strategies in an effort to understand the importance of MKK3 as a p38 MAPK activator. First, I cloned and characterized the murine mkk3 gene and determined the structure of the 5'-terminus. Comparison of the murine and human mkk3 genes revealed that the mouse gene encodes a single MKK3 isoform, MKK3b, and the human gene encodes two isoforms, MKK3a and MKK3b. Comparison of the mouse and human mkk3 genes suggests that expression of MKK3a and MKK3b is regulated from different promotors. Analysis of the mkk3 promoter demonstrates that muscle specific expression of murine MKK3b is controlled, in part, by the transcription factors MEF2 and MyoD. Second, I have utilized a gene targeting strategy to disrupt the murine mkk3 gene and to examine the effect on p38 MAPK signaling. I found that there is a p38-specific signaling defect in MKK3 deficient primary mouse embryo fibroblasts (MEF) which correlates with deficits in interleukin (IL)-1 and IL-6 production in response to tumor necrosis factor-α (TNFα) stimulation. In addition there is a defect in TNFα mediated expression of TNFα and macrophage inflammatory proteins (MIP) 1α, MIP1β and MIP2. p38 MAPK-specific signaling defects were also observed in lipopolysaccharide (LPS) stimulated mkk3 (-/-) macrophages. Additionally, mkk3 (-/-) macrophages exhibit defects in LPS and CD40-ligand (CD40L) stimulated IL-12 biosynthesis. Similar data were obtained from CD40L-stimulated mkk3 (-/-) dendritic cells. I also observe that interferon (Ifn)-γ production is diminished during T-helper-1 (TH1) differentiation of CD4+ T-cells derived ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| اللغة: | English |
| Relation: | http://hdl.handle.net/20.500.14038/31485; https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1184&context=gsbs_diss&unstamped=1; https://escholarship.umassmed.edu/gsbs_diss/184; 225991; gsbs_diss/184 |
| DOI: | 10.13028/mk2q-1b09 |
| الاتاحة: | https://doi.org/10.13028/mk2q-1b09 https://hdl.handle.net/20.500.14038/31485 https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1184&context=gsbs_diss&unstamped=1 https://escholarship.umassmed.edu/gsbs_diss/184 |
| Rights: | Copyright is held by the author, with all rights reserved. |
| رقم الانضمام: | edsbas.D6630D91 |
| قاعدة البيانات: | BASE |
| DOI: | 10.13028/mk2q-1b09 |
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