RRM
2008 Rustbelt RNA Meeting
RRM
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Poster abstracts
Abstract:
Estrogens are steroid hormones that are key regulators of a wide variety of biological processes including growth, development and reproduction. Biological effects of estrogen are mediated through estrogen receptor &alpha and &beta, members of the nuclear receptor family of transcriptional activators (1). While there has been a tremendous progress in deciphering transcriptional mechanisms of estrogen action less is known about its overall impact on mRNA decay even though this comprises one of the major mechanisms regulating gene expression.
In Xenopus hepatocytes estrogen activates a polysome-associated endonuclease, PMR1 that catalyzes the coordinate destabilization of the serum protein mRNAs (2). We previously showed that PMR1 forms a specific complex with its translating target mRNAs, is activated to initiate mRNA decay and also identified that tyrosine phosphorylation by c-Src kinase is involved in allowing PMR1 to bind to polysomes bearing its translating substrate mRNA (3,4). However the mechanism that activates polysome bound PMR1 is not known. This project seeks to characterize the ER activation of PMR1 mediated mRNA decay, probe into the phosphorylation events and link these to the signal transduction pathway[s] activated by between estrogen binding to its receptor. Importantly, we identified an LXXLL nuclear receptor-binding motif in PMR1 and found that ER&alpha and PMR1 interact in vivo. Interestingly we also found that this interaction is modulated by E2 in a time dependent manner. We know from previous work that binding to polysomes is not enough to activate PMR1-mediated mRNA decay, and the recovery of ER&alpha with PMR1 raises the novel possibility that ligand-bound receptor activates mRNA decay by binding directly to the effector mRNA endonuclease.
The central hypothesis of this proposal is that estrogen causes ER&alpha to bind to the PMR1-substrate complex, thus activating the decay of a selective set of growth-regulatory mRNAs. There is no precedent for this in literature and it has opened a whole new direction of possibilities involved in the signal transduction events associated with E2 induced PMR1 mediated mRNA decay.
References:
1. Deroo BJ, Korach KS. (2006) Estrogen receptors and human disease. J Clin Invest.116, 561-70.
2. Dompenciel RE, Garnepudi VR and Schoenberg DR. (1995) Purification and characterization of an estrogen-regulated Xenopus liver polysomal nuclease involved in the selective destabilization of albumin mRNA. J. Biol. Chem. 270, 6108–6118.
3. Yang F, Schoenberg DR. (2004). Endonuclease-mediated mRNA decay involves the selective targeting of PMR1 to polyribosome-bound substrate mRNA. Mol Cell. 14, 435-45.
4. Peng Y, Schoenberg DR. (2007). c-Src activates endonuclease-mediated mRNA decay. Mol Cell. 25, 779-87.
Keywords: Estrogen receptor, PMR1, mRNA decay
