GSBS Dissertations and Theses
Publication Date
2008-06-04
Document Type
Doctoral Dissertation
Academic Program
Cancer Biology
Department
Department of Cancer Biology
First Thesis Advisor
Dario C. Altieri, M.D.
Keywords
Neoplasm Proteins, Signal Transduction, Breast Neoplasms, Insulin-Like Growth Factor I, Receptor, Notch1
Abstract
The 21st century brought about a dramatic increase in knowledge about genetic and molecular profiles of cancer. This information has validated the complexity of tumor cells and increased awareness of “nodal proteins”, but has yet to advance the development of rational targeted cancer therapeutics. Nodal proteins are critical cellular proteins that collect biological inputs and distribute the information across diverse biological processes. Survivin acts as a nodal protein by interfacing the multiple signals involved in mitosis and apoptosis and functionally integrate proliferation, cell death, and cellular homeostasis. By characterizing survivin as a target of both Type 1 Insulin-like Growth Factor (IGF-1) and Notch developmental signaling, we contribute to the paradigm of survivin as a nodal protein. The two signaling systems, Notch and IGF-1, regulate survivin by two independent mechanisms. Notch activation induces survivin transcription preferentially in basal breast cancer, a breast cancer subtype with poor prognosis and lack of molecular therapies. Activated Notch binds the transcription factor RBP-Jк and drives transcription from the survivin promoter. Notch mediated survivin expression increases cell cycle kinetics promoting tumor proliferation. Inhibition of Notch in a breast xenograft model reduced tumor growth and systemic metastasis. On the other hand, IGF-1 signaling drives survivin protein translation in prostate cancer cells. Binding of IGF-1 to its receptor activates downstream kinases, mammalian target of rapamycin (mTOR) and p70 S6 protein kinase (p70S6K), which modulates survivin mRNA translation to increase the apoptotic threshold. The multiple roles of survivin in tumorigenesis implicate survivin as a rational target for the “next generation” of cancer therapeutics.
Repository Citation
Lee, CW. Notch-1 and IGF-1 as Survivin Regulatory Pathways in Cancer: A Dissertation. (2008). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 377. DOI: 10.13028/5fpk-td89. https://escholarship.umassmed.edu/gsbs_diss/377
DOI
10.13028/5fpk-td89
DOI Link
Rights and Permissions
Copyright is held by the author, with all rights reserved.
Included in
Amino Acids, Peptides, and Proteins Commons, Hormones, Hormone Substitutes, and Hormone Antagonists Commons, Neoplasms Commons, Skin and Connective Tissue Diseases Commons