Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, PhD
Ras; RASSF1A; DAB2IP; lung cancer
Ras is the most frequently activated oncogene in human cancer. It is not only the most frequently mutated oncogene, but is also rendered hyperactive in the wild-type form by aberrant regulation. Ras drives transformation and contributes to tumor aggressiveness by activating multiple downstream mitogenic effectors. Ras also possesses the paradoxical ability to induce apoptosis and senescence. Ras-induced apoptosis is not well understood, but has been largely attributed to the RASSF tumor suppressors, particularly RASSF1A. RASSF1A mediates Ras-induced apoptosis by activating pro-apoptotic proteins such as the MST kinases and BAX. RASSF1A is among the most frequently inactivated tumor suppressors in human cancer. Loss of RASSF1A expression by promoter hypermethylation uncouples Ras from its pro-apoptotic effectors, thus promoting unrestrained Ras mitogenic signaling. More recently, it has been suggested that RASSF1A may be not only an apoptotic effector for Ras, but also a general inhibitor of Ras activity. Several groups have reported modulation of Ras mitogenic signaling in response to RASSF1A suppression. However, the mechanism by which this occurs has not yet been elucidated. This dissertation establishes a novel, endogenous interaction between RASSF1A and an important negative regulator of Ras, the RasGAP DAB2IP. We show that RASSF1A expression is an important determinant of DAB2IP protein levels. Loss of RASSF1A dramatically downregulates DAB2IP. This results in increases in Ras-GTP levels, Ras mitogenic pathway activation, and cell proliferation in both wild-type and mutant Ras lung cancer cells. This is the first example of a Ras effector regulating a Ras inhibitor, and the first example of a Ras effector influencing the activation state of Ras.
Harrell Stewart, Desmond Ramón, "A novel role for RASSF1A in the regulation of RAS activation." (2020). Electronic Theses and Dissertations. Paper 3505.
Retrieved from https://ir.library.louisville.edu/etd/3505