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Roles of the Unfolded Protein Response in Cultured Cells and Transgenic Murine Models.

dc.contributor.authorWu, Junen_US
dc.date.accessioned2008-01-16T15:04:36Z
dc.date.available2008-01-16T15:04:36Z
dc.date.issued2007en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/57596
dc.description.abstractWhen protein folding in the endoplasmic reticulum(ER) is disrupted by alterations in homeostasis in the ER lumen, eukaryotic cells activate a series of signal transduction cascades that are collectively termed the Unfolded Protein Response(UPR). To date there are three identified proximal sensors of the UPR: PERK, IRE1alpha and ATF6alpha. Studies with cells and transgenic mice harboring mutations in selective UPR components have contributed significantly to understanding the physiological roles of each UPR pathways. To elucidate the unique role for ATF6alpha in ER function, we have deleted the Atf6alpha gene in mice. ATF6alpha is required for maximal ER stress-mediated induction of genes involved in ER protein folding, trafficking, and surprisingly, ER-associated degradation(ERAD). Although these processes are regulated by ATF6alpha-independent mechanisms as well, Atf6alpha-/- cells cannot mount a full adaptive UPR and exhibit increased sensitivity to chronic stress. These results suggest that the ATF6alpha pathway evolved to protect cells from chronic stress, and provide a rationale for the overlap amongst the three UPR pathways. CREBH was recently identified as an ER stress-induced basic leucine Zipper (bZIP) transcription factor that shares significant structural homology with ATF6alpha. Here we found in response to bacterial lipopolysaccharide(LPS) or the challenge with the ER stressor tunicamycin(TM) that the expression and secretion of acute phase response (APR) markers were significantly reduced in CREBH knockdown mice compared to control mice. This and other findings suggest an intimate relationship between inflammatory responses and ER stress responses. The PERK/eIF2alpha pathway couples protein synthesis with ER protein folding capacity. Mice with a hepatocyte-specific homozygous mutation at the PERK-phosphorylation site in eIF2alpha(Ser51Ala) exhibited significantly reduced liver injury upon LPS + Galactosamine(LPS+GalN) challenge compared to control mice. This in vivo protection was correlated with the defective upregulation of CHOP expression upon LPS+GalN challenges. These findings suggest that pharmacological modulation of eIF2alpha phosphorylation may provide therapeutic benefit during fulminate hepatitis or hemorrhagic shock. Taken together, this work in cultured cells and transgenic murine models has provided insight into the physiological roles of the UPR and encourages further studies towards the development of therapeutic avenues to modulate the UPR in different disease states.en_US
dc.format.extent1373 bytes
dc.format.extent11569112 bytes
dc.format.mimetypetext/plain
dc.format.mimetypeapplication/pdf
dc.language.isoen_USen_US
dc.subjectEndoplasmic Reticulumen_US
dc.subjectATF6en_US
dc.subjectCellular Stressen_US
dc.subjectAdaptation to Chronic Stressen_US
dc.titleRoles of the Unfolded Protein Response in Cultured Cells and Transgenic Murine Models.en_US
dc.typeThesisen_US
dc.description.thesisdegreenamePhDen_US
dc.description.thesisdegreedisciplineBiological Chemistryen_US
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studiesen_US
dc.contributor.committeememberKaufman, Randal J.en_US
dc.contributor.committeememberFuller, Robert S.en_US
dc.contributor.committeememberGinsburg, Daviden_US
dc.contributor.committeememberMeisler, Miriam H.en_US
dc.contributor.committeememberSaltiel, Alan R.en_US
dc.contributor.committeememberXu, Zhaohuien_US
dc.subject.hlbsecondlevelBiological Chemistryen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.subject.hlbtoplevelScienceen_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/57596/2/wujunz_1.pdfen_US
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


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