Show simple item record

dc.contributor.authorCornwell, Evangeline Wangen_US
dc.date.accessioned2015-04-24T19:50:28Z
dc.date.available2015-04-24T19:50:28Z
dc.date.issued2014
dc.date.submitted2014
dc.identifier.other
dc.identifier.urihttps://hdl.handle.net/2144/10972
dc.descriptionThesis (Ph.D.)--Boston Universityen_US
dc.description.abstractExisting data suggest that NF-kappaB signaling is a key regulator of cancer-induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-kappaB transcription factors that regulate wasting is far from complete. In muscles of C26 tumor-bearing mice, overexpression of dominant-negative (d.n.) IKKbeta and the IkappaBalpha-super repressor blocked wasting by 69% and 41%, respectively. In contrast, overexpression of d.n. IKKalpha or d.n. NIK did not block C26-induced muscle wasting. Surprisingly, overexpression of d.n. RelA (p65) or d.n. c-Rel did not significantly affect muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-kappaB transcription factors, we compared genome-wide p65 binding to DNA in control and cachectic muscle using chromatin immunoprecipitation-sequencing (ChiP-seq). Bioinformatic analysis of ChiP-sequencing data from control and C26 muscles did not show p65 binding peaks in the upregulated genes as reflected by the expression arrays. The p65 ChiP-seq data are consistent with our finding of no significant change in protein binding to an NF-kappaB oligonucleotide in an electrophoretic mobility shift assay (EMSA), no activation of an NF-kappaB-dependent reporter, and no effect of d.n. p65 overexpression in muscles of tumor-bearing mice. Taken together, these data support the idea that although inhibition of IkappaBalpha, and particularly IKKbeta, blocks cancer-induced muscle wasting, the alternative NF-kappaB signaling pathway is not required. In addition, the downstream NF-kappaB transcription factors are not involved in gene regulation during atrophy. These data are consistent with the growing body of literature showing that there are NF-kappaB-independent activities of IKKbeta and IkappaBalpha that regulate physiological processes.en_US
dc.language.isoen_US
dc.publisherBoston Universityen_US
dc.titleColon-26 cancer-induced skeletal muscle wasting is IKKbeta/IkappaBalpha-dependent and NF-kappaB-Independenten_US
dc.typeThesis/Dissertationen_US
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineHealth Sciencesen_US
etd.degree.grantorBoston Universityen_US


This item appears in the following Collection(s)

Show simple item record