mRNA decay plays a key role in regulating the expression of many hormone-regulated genes, transcription factors, growth factors, cytokines and protooncogenes. For many mRNAs decay involves exonucleasemediated mechanisms involving either 3'-5' decay or removal of the 5' cap followed by 5'-3' decay. The latter process occurs in discrete cytoplasmic foci termed P-bodies. A number of hormone-regulated mRNAs are degraded through a distinctly different mechanism involving endonuclease cleavage within the coding region or the 3'-UTR. PMR1 was identified as an estrogen-induced endonuclease activity in Xenopus liver that catalyzes the selective degradation of serum protein mRNAs. PMR1 is not present in P-bodies, but instead is a component of approximately 680 kDa complex with its translating, polysome-bound substrate mRNA. It is in this context that it is activated to initiate mRNA decay by endonucleolytic cleavage within the mRNA body. The long-term goal of this work is to understand the molecular mechanisms of PMR1-mediated mRNA decay and their implication for controlling gene expression during development, in response to hormonal stimuli, and in malignancy. PMR1 must be tyrosine phosphorylated to target and degrade its polysome-bound substrate mRNA. This represents a novel link between signal transduction and mRNA decay.
The Specific Aims for this renewal application are; 1) to characterize the functional domains of PMR1 and their role in mRNA decay, 2) to identify the PMR1 tyrosine kinase and characterize its role in 'licensing' PMR1 to target arid degrade its translating substrate mRNA, 3) to identify and characterize the protein components of the functional complexes that participate in PMR1-mediated mRNA decay, and 4) to identify the mRNA targets of PMR1. PMR1 is the first effector of mRNA decay shown to be a direct target of signal transduction, and its requirement for tyrosine phosphorylation links endonuclease-mediated mRNA decay to the disregulation of gene expression characteristic of cancer.
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