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dc.contributor.advisorHu, Cheng-Jun
dc.contributor.authorPawlus, Matthew
dc.date.accessioned2007-01-03T04:53:21Z
dc.date.available2007-01-03T04:53:21Z
dc.date.submitted2013
dc.identifierPawlus_ucdenveramc_1639D_10026.pdf
dc.identifier.urihttp://hdl.handle.net/10968/258
dc.descriptionSpring
dc.descriptionIncludes bibliographical references.
dc.description.abstractIn response to hypoxia, cells mediate expression of genetic programs through stabilization of HIF1α and HIF2α hypoxia inducible transcription factors. Activation of HIF target genes promotes cell proliferation, apoptotic resistance, metabolic adaptation, and tissue angiogenesis in normal physiologic as well as pathophysiologic processes including tumorigenesis. Data suggests that HIF1 and HIF2 play different roles in cancers derived from different types of tissues, sometimes even opposing each other's function. While reported differences in target gene specificity between HIF1 and HIF2 likely explain their varying roles, a mechanism explaining how HIF target gene specificity is achieved has been lacking. Importantly, discovery of this mechanism is necessary for the development of specific pharmacologic inhibitors of HIF1 or HIF2 activity. The following work demonstrates for the first time that HIFs function in distinct transcriptional complexes containing the HIF1 specific co-activator, STAT3, or the HIF2 specific co-activator, USF2 on their target gene promoters. Importantly, the identified HIF-specific co-activators function to enhance HIF-mediated target gene transactivation through recruitment of CBP and P300 co-activators, as well as selectively determine which HIF is included in the functional POL II-containing transcriptional complex on HIF target gene promoters. Our findings importantly provide a novel molecular mechanism through which HIF target gene specificity is determined by HIF interaction with specific transcriptional complexes and provides alternative targets that may be exploited to specifically inhibit HIF activity in tumorigenesis.
dc.languageEnglish
dc.language.isoeng
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.subjectUSF
dc.subjectenhanceosome
dc.subject.meshSTAT3 Transcription Factor
dc.subject.meshAnoxia
dc.subject.meshHypoxia-Inducible Factor-Proline Dioxygenases
dc.subject.meshCarcinogenesis
dc.titleRole of co-activating factors in the HIF-mediated hypoxia response, The
dc.typeThesis
dc.contributor.committeememberReyland, Mary
dc.contributor.committeememberHeasley, Lynn
dc.contributor.committeememberBentley, David
dc.contributor.committeememberHuang, Mingxia
dc.contributor.committeememberFord, Heide
thesis.degree.nameDoctor of Philosophy (Ph.D.)
thesis.degree.levelDoctoral
thesis.degree.disciplineMolecular Biology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus


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