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Disruption of Transcription by the Oncogene PML-RARα in Acute Promyelocytic Leukemia and Regulation of the Tumor Suppressor PML in Breast Cancer

Reineke, Erin Lynn
http://rave.ohiolink.edu/etdc/view?acc_num=case1207230023

Abstract Details

2008, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Acute Promyelocytic Leukemia (APL) accounts for about 3% of leukemia cases each year. Although treatment is currently available for these patients, side effects from these treatments could be decreased by using treatments that directly target the abnormalities. In 90% of patients, APL arises from a chromosomal translocation in which the retinoic acid receptor α (RARα) gene is fused with the promyelocytic leukemia (PML) gene. This chromosomal translocation results in the expression of the oncogenic fusion protein PML-RARα. The pathogenesis of APL is driven by disruption of both RARα signaling and PML signaling. We show that one mechanism by which PML-RARα controls RARα signaling is through the sequestration of transcription co-activators. Contrary to RARα, PML-RARα associates with co-activators in the absence of the RARα activating hormone retinoic acid. This ligand-independent association prevents the association of these co-activators with other transcription factors. In this manner, PML-RARα disrupts normal transcriptional regulation. In order to understand how PML signaling is disrupted in APL, it is important to determine how PML is normally controlled. We show that PML is negatively regulated by the peptidyl-prolyl isomerase Pin1. These two proteins interact in a phosphorylation-dependent manner, the consequence of which is a decrease in the stability of PML. In breast cancer cells, decreased levels of PML, which in some cases coincide with elevated levels of Pin1, are important for cell proliferation and resistance to hydrogen peroxide induced cell death. Due to this, we hypothesize that APL cells have lost regulation of a protein that is intimately involved in the regulation of cell fate. It will be important in the future to further characterize exactly what role altered regulation of RARα and PML plays in APL cells. The data presented here provide an important starting point for the development of new therapies that may be important in APL as well as other cancers.
Hung-Ying Kao, PhD (Advisor)
Dave Samols, PhD (Committee Chair)
Martin Snider, PhD (Committee Member)
Peter Harte, PhD (Committee Member)
Pieter deHaseth, PhD (Committee Member)
161 p.
Biochemistry; Molecular Biology
APL; PML; Breast Cancer; RAR

Recommended Citations

Citations

  • Reineke, E. L. (2008). Disruption of Transcription by the Oncogene PML-RARα in Acute Promyelocytic Leukemia and Regulation of the Tumor Suppressor PML in Breast Cancer [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1207230023

    APA Style (7th edition)

  • Reineke, Erin. Disruption of Transcription by the Oncogene PML-RARα in Acute Promyelocytic Leukemia and Regulation of the Tumor Suppressor PML in Breast Cancer. 2008. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1207230023.

    MLA Style (8th edition)

  • Reineke, Erin. "Disruption of Transcription by the Oncogene PML-RARα in Acute Promyelocytic Leukemia and Regulation of the Tumor Suppressor PML in Breast Cancer." Doctoral dissertation, Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1207230023

    Chicago Manual of Style (17th edition)

case1207230023
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© 2008, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.