Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology


English (en)

Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Jason D Weber


Cancer is a complex genetic disease characterized by the inactivation of tumor suppressor genes and enhanced activity of oncogenes leading to deregulated cellular proliferation. Two tumor suppressor genes, p53 and Arf, play important roles in protecting cells against numerous biological stresses. In response to oncogenic signals, increased ARF expression leads to the activation of p53, which in turn leads to the cessation of cell division or induction of an apoptotic response. Interestingly, p53 coordinates repression of Arf transcription, setting up a negative feedback loop with currently unknown physiological significance. Cells that lack p53 express elevated levels of ARF, but it has been generally accepted that these levels serve no tumor suppressor function. This view has been challenged recently as numerous groups have demonstrated ARF can inhibit both cell growth and proliferation independently of p53. Additionally, co-inactivation of p53 and Arf is frequently observed in human cancers, suggesting they do not function in a strictly linear genetic pathway.

The objective of my dissertation was to examine the biological functions of ARF in the absence of p53. I specifically wanted to understand why p53-deficient cells express elevated levels of ARF, and whether these increased levels are able to suppress tumorigenesis. By addressing these questions, I hoped to provide a mechanistic explanation for the selective advantage cancer cells gain by inactivating both p53 and Arf, and ultimately uncover novel therapeutic approaches that could be used to treat patients whose tumors exhibit these specific genetic abnormalities.

My dissertation work utilized an in vitro system to study the role of ARF in cells lacking p53. I hypothesized that acute loss of p53 would lead to an upregulation of ARF which would exert a currently undefined tumor suppressor function. Indeed, I have demonstrated that loss of p53 leads to an induction of ARF, which is able to potently suppress tumorigenesis. Depletion of ARF in this genetic setting lead to the activation of a type I interferon response driven by interferon-beta and the STAT1 transcription factor. I further demonstrated that ARF and p53 cooperate to suppress the interferon response, and when both proteins are inactivated, interferon signaling can drive tumor cell proliferation. Additionally, I have shown that breast cancer cell lines lacking ARF and p53 are sensitive to STAT1 depletion, indicating targeted disruption of this signaling pathway can inhibit cancer cell growth. Finally, I identified a subtype of breast cancer, defined as ER-/PR-/HER2-, that exhibits activation of the interferon signaling pathway in the absence of p53 and ARF function.

This work has solidified ARF's role as a p53-independent tumor suppressor, and provides insight into the selective advantage cancer cells gain by co-inactivating these two tumor suppressor genes. As we enter an era of personalized cancer therapy, a detailed understanding of cancer cell vulnerabilities is imperative. The data presented in this dissertation has identified a subset of patients that would benefit from targeted inhibition of IFN-β signaling. Equally as important, I have identified a novel oncogenic signaling pathway that could be promoting tumor growth in numerous other cancer types.


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