Two barriers to Ras mediated oncogenesis: translational control checkpoint and proliferative block by autophagy.
2009-06
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Two barriers to Ras mediated oncogenesis: translational control checkpoint and proliferative block by autophagy.
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2009-06
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Abstract
According to the American Cancer Society, cancer is the second leading cause of mortality in the United States, accounting for more than half a million deaths per year. Cancer is a complex disease with multiple factors influencing its genesis, maintenance, growth, and invasion which makes the treatment and prevention of the disease challenging. Despite the high mortality and morbidity associated with cancer, it is a disease of the old, with the median age for cancer incidence being 66 years old according to the National Cancer Institute. Therefore, the human body is remarkably adept at protecting itself from malignant transformation. In my thesis, I explore the oncogene Ras which is represented in approximately 30% of all human cancers, making Ras one of the most commonly activated oncogenes. I analyzed the innate barriers to oncogenic Ras (RasV12) induced transformation in the cell in an attempt to better understand tumor defense systems which can be mimicked for novel cancer therapy. My results confirmed one putative barrier which had good experimental grounding and identified a completely new barrier.
One putative barrier to RasV12 oncogenesis was the existence of a translational control check point in tumor defense. Activation of translation initiation has been shown to be on the causal pathway to cancer and is activated by Ras via two different pathways. The rate limiting translation initiation factor 4E (eIF4E) is up regulated in many cancers and over expression of eIF4E confers cells with transformed phenotypes. Therefore, if activation of translation is oncogenic, then it is reasonable to posit the existence of a translational control checkpoint in tumor defense. The logical guardians of this checkpoint would be the primary negative regulators of translational initiation, the eIF4E binding protein (4E-BP) family of proteins. I show that translational control checkpoint does indeed exist in tumor defense and that the 4E-BPs are the guardians of this checkpoint. Mice lacking two of the three 4E-BPs (4ebp1-/-/4ebp2-/-) were more sensitive to tobacco carcinogen NNK induced lung tumors and showed tumors with increased vascularity. Also, 4ebp1-/-/4ebp2-/- genotype was associated with a skewing of the genome wide translational profile towards growth and proliferation even before NNK treatment indicating a cancer primed state. Lastly, I showed that the cytochrome P450 2A5, the protein that metabolizes NNK to its carcinogenic product, was translationally up regulated increasing the carcinogenic potency of NNK.
The second barrier to RasV12 oncogenesis was an unexpected discovery. In an effort to determine the mechanism of RasV12 oncogenesis and its defense, I discovered that RasV12 triggered proliferative block even in cells which have bypassed the senescence barriers. This was unexpected since previous reports had shown that in this setting, RasV12 actually caused anchorage independent growth and invasion in vitro. The nature of the proliferative block was not senescence although it has many of the characters of senescence. Due to a striking phenotypical change where large vacuoles accumulate, I explored the possibility that autophagy was playing a role in the proliferative block. I show that RasV12 expressing cells displayed hallmarks of autophagy such as double membraned vacuoles with pieces of organelles, acidic nature of the vacuoles, and positivity for early and late markers of autophagy.
My study validates the current efforts to develop targeted therapy against the translation initiation complex and provides autophagy as a new potential target for caner therapy. By learning from the cell's innate cancer barriers, I hope that we will be able to develop more effect therapies for cancer.
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University of Minnesota Ph.D. dissertation. June 2009. Major: Microbiology, Immunology and Cancer Biology. Advisor: Peter B. Bitterman, MD. 1 computer file (PDF); xiv, 146 pages. Ill. (some col.)
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Kim, Yong Yean. (2009). Two barriers to Ras mediated oncogenesis: translational control checkpoint and proliferative block by autophagy.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/54529.
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