Doctoral theses
Current Record: 281 of 336
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| Identifier |
uch.biology.phd//1998agalioti |
| Title |
Μελέτη του ρόλου των πρωτεϊνών Ε1Α και CIITA στη μεταγραφή των γονιδίων ιστοσυμβατότητας τάξης |
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Author
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Αγαλιώτη, Θεοδώρα Δ
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Thesis advisor
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Παπαματθαιάκης, Ιωσήφ
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| Abstract |
The Major Histocompatibility Complex (MHC) Class II molecules are surface proteins of central importance for antigen presentation and the regulation of the immune response. MHC Class II molecules are encoded by members of a family of polymorphic genes that show complex cell type specific, developmental and cytokine mediated expression patterns. Class II genes have attracted a lot of scientific interest because of their immunological importance and complex expression. MHC Class II genes are coordinately regulated at the transcriptional level due to a unique combination of well-characterized conserved cis elements found at their proximal promoters called class II boxes (CB) or motifs. The presence and concerted action of all the CBs and their characterized cognate transcription factors (TFs) is necessary, but is not by itself sufficient for gene expression. At a higher regulatory level, the action of the above TFs is integrated by yet another protein factor called the Class II Transactivator protein (CIITA) that determines both the Β cell specific and the interferon-γ (IFNγ) inducible transcriptional activity of Class II genes in cells of macrophage or epithelial origin. The Adenoviral E1A gene has proven to be a valuable tool for the understanding of important aspects of cell cycle regulation. E1A is a dual transcriptional modulator. It acts as transcriptional activator or repressor in many cases of viral and cellular genes. Due to its ability to sequester molecules with properties of transcriptional "adaptors", E1A is known to act as a powerful repressor of transcription. Here we report that E1A represses B cell specific, interferon-γ induced and CIITA dependent transcription, of both mouse and human MHC class II promoters. This ability of E1A resides at both the extreme N-terminal part ( aa 1-20) and the CR1 (aa) domain of the protein. These regions of E1A are known to interact with the "adaptor" molecule p300. Repression cannot be defined to target any single element. Thus, the combinatorial action of the Eα gene promoter CBs is equally subject to activation in B cells or after IFN-γ and repression by E1A. E1A does not interfere with the ability of CIITA access to Class II promoters. Rather, E1A specifically targets the function of CIITA's transcription activation domain. E1A and CIITA do not physically contact each other. Since it has been demonstrated that E1A and CIITA bind to the CH3 domain of the "adaptor" molecule CBP, we propose that E1A inhibits both B cell and IFN-γ mediated class II transcription by disrupting the CBP-CIITA interaction. Furthermore, we show that E1A interferes with «early» events of the IFN-γ signal transduction pathway that depend on the integrity of the Jak-STAT system that in turn, is necessary for the transcriptional induction of CIITA. 293 cells that express E1A are defective in both early and late (Class II) IFNγ response. Inability of 293 cells for class II induction by IFNγ correlates with the absence of CIITA mRNA induction. The action of STAT1α is inhibited in these cells in spite of its normal phosphorylation, transportation to the nucleus, and binding to the target DNA. We present evidence that E1A inhibits the action of STAT1α by targeting its transcriptional activation domain.
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| Language |
Greek |
| Issue date |
1998-10-15 |
| Collection
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School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
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Type of Work--Doctoral theses
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| Permanent Link |
https://elocus.lib.uoc.gr//dlib/f/a/f/metadata-dlib-1998agalioti.tkl
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| Views |
580 |
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