Regulation of the Insulin-like Growth Factor 1-Secretory Clusterin Expression Axis in Genomic Instability and Cell Stress

Simple item page
dc.contributor.advisorBoothman, David A.en
dc.creatorGoetz, Eva Marieen
dc.date.accessioned2010-07-12T18:25:17Z
dc.date.available2010-07-12T18:25:17Z
dc.date.issued2009-09-04
dc.description.abstractSecretory clusterin (sCLU) is a pro-survival factor that is up-regulated in human tumors and after exposure to cell stress. Understanding the regulation of sCLU expression in cancer, and after exposure to therapeutic agents, could reveal new therapeutic targets for cancer treatment. A DNA damage induced signaling cascade leading from ATM to sCLU expression mediated by IGF-1/IGF-1R/MAPK activation was uncovered. IGF-1 ligand promoter activity, mRNA, and protein expression induced after exposure to ionizing radiation (IR), hydrogen peroxide, or topoisomerase I and II-alpha poisons matched sCLU expression. Elevated basal IGF-1-sCLU signaling was noted in genomically unstable cells, whether they were deficient in DNA repair factors or telomerase function. ATM function was necessary for induction of sCLU after IR, and for maintaining elevated expression of sCLU in genomically unstable cells. p53 suppressed IGF-1 promoter activity, leading to decreased mRNA and protein expression, and abrogated induction of IGF-1 and sCLU by IR. Loss of p53 by knockdown or knockout enhanced IGF-1 and sCLU induction. Mutations in the p53 DNA binding domain found in cancer did not repress IGF-1 and sCLU. An NF-Y binding site in the IGF-1 promoter was essential for p53 suppression, and both p53 and NF-YA bound to the IGF-1 promoter. Nutlin-3, an Mdm2-p53 inhibitor, stabilized p53 expression, leading to dramatically decreased sCLU expression. Nutlin-3 treatment sensitized wild-type p53 cells to IR exposure. Finally, exogenous IGF-1 exposure led to serine 1981 auto-phosphorylation of ATM, and enhanced DNA damage repair and abrogated cell death after IR exposure. These studies uncovered key molecules important for the regulation of IGF-1-sCLU expression axis after IR exposure, and supported the use of IGF-1 or sCLU expression inhibitors for cancer chemotherapy.en
dc.format.digitalOriginborn digitalen
dc.format.mediumElectronicen
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc760300248
dc.identifier.urihttps://hdl.handle.net/2152.5/546
dc.language.isoenen
dc.subjectCell Cycle Proteinsen
dc.subjectClusterinen
dc.subjectDNA Damageen
dc.subjectDNA-Binding Proteinsen
dc.subjectGene Expression Regulation, Neoplasticen
dc.subjectGenomic Instabilityen
dc.subjectInsulin-Like Growth Factor Ien
dc.subjectNeoplasmsen
dc.subjectProtein-Serine-Threonine Kinasesen
dc.subjectTumor Suppressor Proteinsen
dc.titleRegulation of the Insulin-like Growth Factor 1-Secretory Clusterin Expression Axis in Genomic Instability and Cell Stressen
dc.typeThesisen
dc.type.genredissertationen
dc.type.materialTexten
thesis.date.available2011-09-04
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCell Regulationen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
goetzeva.pdf
Size:
11.56 MB
Format:
Adobe Portable Document Format
Download

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
942 B
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

UT Southwestern Graduate School of Biomedical Sciences