Characterization of the ARF Tumor Suppressor's Checkpoint Response to Hyper-Growth Stimuli

Date of Award

Spring 5-15-2012

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Loss of the regulatory networks that monitor cellular growth and proliferation is among the cascade of mechanistic events responsible for driving cancer. The alternative reading frame (ARF) tumor suppressor is pivotal for the regulation of these key biological processes. ARF is a potent sensor of oncogenic stimuli in the cell. ARF induces a cell cycle arrest, through both p53-dependent and -independent manners, to abate the tumorigenic potential of these hyperproliferative stimuli. The significance of ARF tumor suppression is reinforced by the observation that the locus encoding ARF is either deleted or silenced at an extremely high rate in human cancers. The main objectives of my dissertation research are to better understand the array of oncogenic stimuli that is susceptible to ARF tumor surveillance and to better comprehend the mechanism by which ARF can respond to oncogenic stimuli. Better discernment of ARF's responsiveness to oncogenic cues will further our insight into how cells evade the requisite regulatory network of ARF tumor suppression during tumorigenesis.

At the onset of my dissertation research, the means by which ARF could mediate its critical tumor surveillance in the absence of cooperating transcriptional activation remained poorly understood. It had been demonstrated that the Ras/Raf/MEK/ERK signaling pathway was responsible for activating the Dmp1 transcription factor, which in turned increased the de novo synthesis of Arf mRNA transcripts in response to oncogenic RasV12 signaling. However, ARF is still capable of responding to oncogenic RasV12 in the absence of Dmp1. The mechanisms driving this ARF induction and whether ARF was functional against oncogenic cues in the absence of Dmp1 remained unclear. I hypothesized that another pathway downstream of Ras played an important role in regulating ARF's levels and tumor suppressive functions. Given ARF's central role in sensing hyperproliferative signals, I hypothesized that ARF might be also sensitive to the hypergrowth cues emanating from mTORC1 signaling.

The data gathered in this dissertation demonstrate that the Ras/Raf/MEK/ERK signaling pathway does not exclusively mediated ARF's induction from oncogenic RasV12 signaling, and that the PI3K/TSC/mTORC1 signaling pathway can regulate ARF through a novel translational mechanism. Hyperactivation of the mTORC1 induces a robust ARF induction, a dramatic cell cycle arrest, and repression of cellular transformation and tumorigenesis. Moreover, the molecular mechanism driving the translational regulation of ARF through mTORC1 signaling can be attributed to the action of a microRNA, miR-760. Taken together, these data suggest a novel and significant role for ARF tumor suppression as acting as a cellular checkpoint against excessive pro-growth stimuli.

This work has provided unique insights into ARF tumor suppression. Because the inactivation of ARF and suppressors of the mTOR pathway are common targets in cancer initiation and development, it is important to understand the role of these proteins on proliferation and growth. Manipulation of the ARF mediated growth checkpoint in cancer cells could have significant impact on the development of new therapeutic options for cancer patients.


English (en)

Chair and Committee

Jason D Weber

Committee Members

David Beebe, Jeffrey Arbeit, Ron Bose, Fanxin Long, Zhongsheng You


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