Matching Items (2)
Description
The p53 gene functions as a tumor suppressor that inhibits proliferation, regulates apoptosis, DNA repair, and normal cell cycle arrest. Mutation of the p53 gene is linked to be prevalent in 50% of all human cancers. In this paper, we are exploring triple negative breast cancer and the effects of simvastatin on tumor growth and survival. Simvastatin is a drug that is primarily used to treat high cholesterol and heart disease. Simvastatin is unique because it is able to inhibit protein prenylation through regulation of the mevalonate pathway. This makes it a potential targeted drug for therapy against p53 mutant cancer. The mechanism behind this is hypothesized to be correlated to aberrant activation of the Ras pathway. The Ras subfamily functions to transcriptionally regulate cell growth and survival, and will therefore allow for a tumor to thrive if the pathway is continually and abnormally activated. The Ras protein has to be prenylated in order for activation of this pathway to occur, making statin drug treatment a viable option as a cancer treatment. This is because it acts as a regulator of the mevalonate pathway which is upstream of protein prenylation. It is thus vital to understand these pathways at both the gene and protein level in different p53 mutants to further understand if simvastatin is indeed a drug with anti-cancer properties and can be used to target cancers with p53 mutation. The goal of this project is to study the biochemistry behind the mutation of p53's sensitivity to statin. With this information we can create a possible signature for those who could benefit from Simvastatin drug treatment as a possible targeted treatment for p53 mutant cancers.
ContributorsGrewal, Harneet (Co-author) / Loo, Yi Jia Valerie (Co-author) / Anderson, Karen (Thesis director) / Blattman, Joseph (Committee member) / Ferdosi, Shayesteh (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Abstract: The RAS/RAF/MEK/ERK (RAS signaling cascade) pathway is a highly conserved biochemical signaling cascade that exists in every mammalian cell. The pathway is highly versatile in functionality due to hundreds of substrates that regulate metabolism, apoptosis, and proliferation in both adult and developing tissues. The RAS signaling cascade has been examined in the context of cancers since mutations can lead to the disruption of the cell cycle and unregulated cellular proliferation. In addition, germline mutations in the pathway have been shown to cause a group of syndromes known as RASopathies. RASopathies are marked by facial defects, seizures, developmental delays, and cognitive dysfunction often due to enhanced activation of the RAS signaling cascade. Although there are noted factors that play roles in neurological disease, such as a hyperactivated RAS signaling cascade, the pathogenesis of neurological defects is not fully understood. The Newbern lab uses conditional mutagenesis to examine how hyperactivating the RAS/MAPK pathway affects GABAergic neurons in a cortical microcircuit, especially during development. Inhibitory neurons are implicated in seizures and epilepsy is common in RASopathies, thus GABAergic neurons are of particular interest (Rauen, 2013). Gain-of-function ERK was not found to significantly alter global locomotion or anxiety-like behaviors. Interestingly, the mutant mice exhibited freezing behavior in the first twenty-two seconds of the open field assay that appeared to be consistent with absence seizures. Direct EEG recordings confirmed spontaneous seizure activity and mutants had a reduced seizure threshold. We hypothesized that these deficits were due to altered GABAergic neuron number. Indeed, mutant mice exhibited a 30% reduction in total cortical GABAergic neuron number. This effect appeared to be cell subtype specific, where neurons expressing somatostatin (SST) existed in similar numbers among controls and mutants but a significant decrease in the number of those expressing parvalbumin (PV) was observed. I hypothesized that a recently identified GABAergic neuron expressing vasoactive intestinal polypeptide (VIP) would also be affected in such a manner that fewer VIP neurons exist in the mutants than the wildtype. Subsequent histological studies in these mice found there to be no significant difference in VIP populations. Selective affects seem to only have an effect on the development of PV neurons in the cortex. Further studies are underway to define the mechanism responsible for aberrant GABAergic neuron development.
ContributorsGonzalez, Javier (Author) / Newbern, Jason (Thesis director) / Neisewander, Janet (Committee member) / Barrett, The Honors College (Contributor)
Created2016-05