The Effects of Poly (A)-Binding Protein 1 (PABP1) Over-Expression on MRNA Metabolism and the Regulation of PABP1 Expression Following Recovery from Heat Shock
University of Guelph, 2008 - 152 pages
Cytoplasmic poly (A)-binding protein (PABP1) plays crucial roles in mRNA translation and stability, and its expression is tightly regulated. Previous studies found the cellular level of 19 mRNAs was reduced in PABP1 over-expressing cells. This thesis explores some of the mechanistic relationships between PABP1 over-expression and the regulation of specific mRNAs, and also the regulation of PABP1 expression under heat shock. One objective examined the mechanism by which PABP1 expression reduced the level of mitogen-activated protein kinase kinase 2 (MKK2) mRNA. This particular gene was chosen because it functions in the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and its perturbation is implicated in cellular transformation and human cancer. The specific hypothesis being tested is that PABP1 binding to a specific region of the MKK2 mRNA induces degradation of the transcript. This hypothesis was examined by UV cross-linking of PABP1 and MKK2 mRNA. This approach revealed a novel stability control element in the 3' untranslated region of the MKK2 mRNA that binds PABP1. The control element decreases the stability of a reporter mRNA in PABP1 over-expressing cells. Furthermore, it was also determined that PABP1 was hypo-phosphorylated in PABP1 over-expressing cells, and that the MKK2-ERK1/2 kinase pathway was involved in the phosphorylation of PABP1.
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