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The impact of phosphoprotein enriched in astrocytes (pea15) on tumor development and progression

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Item Summary

Title: The impact of phosphoprotein enriched in astrocytes (pea15) on tumor development and progression
Authors: Sulzmaier, Florian Johannes
Keywords: phosphoprotein
Issue Date: Dec 2012
Publisher: [Honolulu] : [University of Hawaii at Manoa], [December 2012]
Abstract: Phosphoprotein enriched in astrocytes, 15 kDa (PEA15) is a small death effector domain-containing protein that has been described to fulfill both tumorsuppressing and tumor-promoting functions depending on the cellular context. For example, PEA15 can increase cancer cell survival by protecting tumor cells from apoptosis induced by glucose deprivation. This promotes tumor growth. Alternatively, PEA15 blocks activation of nuclear targets of the extracellular signal regulated kinase (ERK) by sequestering ERK in the cytoplasm. Thereby PEA15 can prevent tumor cell proliferation and negatively regulate cell migration.
In this thesis, I characterized the underlying mechanisms and pathways that mediated these opposite PEA15 functions. I analyzed PEA15 in scenarios in which it functioned by either promoting tumor formation in kidney epithelial cells or blocked tumor progression in glioblastoma cells. I found that PEA15 enhanced H-Ras mediated transformation of immortalized mouse kidney epithelial cells by enhancing the ERK/MAPK pathway through increased PLD1 signaling. This resulted in elevated levels of cell cycle regulatory proteins and accelerated G1/S cell cycle transition driving cell transformation. In contrast, in glioblastoma cells PEA15 blocked tumor progression. The protein inhibited cell migration and I found that PEA15 acted at least in part by increasing the activity of the ERK target RSK2. Increased RSK2 activity led to the observed reduction in cell motility.
My work provides further novel insight into how the same protein can cause two completely opposite functional outcomes depending on the cellular environment. My findings help to characterize PEA15's diverse cellular functions and to elucidate its mode of action. This work thereby defines new contexts to be considered to better evaluate PEA15's use as a prognostic marker or potential therapeutic target.
Description: Ph.D. University of Hawaii at Manoa 2012.
Includes bibliographical references.
Appears in Collections:Ph.D. - Molecular Biosciences and Bioengineering

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