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" Inhibitor function and phosphoregulation of thep105 precursor ofp50 rel "
M. L. Mackichan
A. J. Israel, Patricia
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Latin Dissertation
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English
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| Record Number
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1113230
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| Doc. No
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TLpq304302613
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| Main Entry
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A. J. Israel, Patricia
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M. L. Mackichan
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| Title & Author
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Inhibitor function and phosphoregulation of thep105 precursor ofp50 rel\ M. L. MackichanA. J. Israel, Patricia
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| College
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Stanford University
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| Date
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1996
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| student score
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1996
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| Degree
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Ph.D.
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| Page No
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212
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| Abstract
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The rel proteins are a ubiquitously expressed family of transcription factors that specifically bind as homo- or heterodimers to a DNA sequence called the usd\kappausdB site. Binding sites for these factors contribute to the expression of many cellular target genes, notably receptors and cytokines important for immune system function, and several viruses, including the human immunodeficiency virus. In most cells the rel proteins are sequestered in the cytoplasm by associated inhibitor subunits, the Iusd\kappausdBS, and are only released to the nucleus upon receipt of a specific signal. The rel transcription factors are a multisubunit family that share a 300-amino acid region called the rel homology domain (RHD). A common usd\kappausdB binding activity, NF-usd\kappausdB, is composed of the p50 and p65 rel proteins. The p50 subunit is synthesized as a precursor protein of 105 kd, which contains multiple ankyrin repeats in the C-terminal half. Ankyrin repeats are also the major feature of the Iusd\kappausdBs. In contrast to p50, the p105 precursor is exclusively cytoplasmic and cannot bind to DNA. p50 is derived from p105 by proteolysis of the C-terminal half of the precursor. In collaboration with N. Rice (NCI), we showed that the p105 precursor functions as an inhibitor of other rel proteins, retaining them in the cytoplasm. We demonstrated that the cytoplasmic p105/rel protein complexes give rise, via proteolytic processing of the precursor, to nuclear p50/rel dimers. We next studied the regulation of this event in a model of T cell activation. We found that treatment of T cell activation upregulates the processing of p105 to p50 and is correlated with an increase in phosphorylation of p105. The increased phosphorylation occurs on multiple serines in the extreme C-terminus of p105 following the ankyrin repeats, a domain rich in P, E, S, and T residues. The PEST domain is also required for the stimulus-induced processing of p105, suggesting increased phosphorylation renders the protein more susceptible to this proteolysis. Like p105, another rel inhibitor, Iusd\kappausdBusd\alphausd, is regulated by phosphorylation and ensuing proteolysis. However, the signalling pathways leading to phosphorylation of the two inhibitors are not identical, as p105 phosphorylation is unaffected by antioxidants that block Iusd\kappausdBusd\alphausd phosphorylation.
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Biological sciences
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kappa
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Molecular biology
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NF
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