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Dissecting the Molecular Mechanisms of the Alternative Nuclear Export and Endoplasmic Reticulum Targeting of Secretory mRNAs.

Alexander Palazzo

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Canadian Institutes of Health Research (CIHR)
During gene activation, segments of DNA are transcribed into messenger RNA (mRNA) in the nucleus. These RNA transcripts are processed, exported into the cytoplasm and then delivered to particular regions, depending on elements that are found within each mRNA. After arriving at their proper subcellular destination, the mRNAs are then translated into proteins. In order to be exported from the nucleus and then localized to particular regions, each mRNA must acquire particular protein factors that assist them at each of these steps. It however remains unclear how different mRNAs acquire these protein factors. The majority of mRNAs code for "cytosolic" proteins, which remain within the cell. However, a substantial fraction of mRNAs, originating from 15-20% of all human genes, are targeted to the surface of the endoplasmic reticulum (ER), where they are translated into proteins that must cross a membrane. These "secretory proteins" are either delivered to the interior of an organelle, or exported to the extra-cellular environment. My lab has been studying how cells regulate the transport and distribution of mRNAs encoding secretory proteins. We have discovered that mRNAs encoding secretory proteins contain a number of RNA elements that confer special properties to the transcript. One of these elements promotes the nuclear export of these secretory mRNAs. A second mechanism helps to target and then anchor these mRNAs to the surface of the ER. We have uncovered proteins that are required for the nuclear export and the ER-anchoring of these mRNAs. In this proposal I will outline my plans to dissect the molecular mechanisms underlying these two processes. Since the pathways we discovered regulate the expression of secretory proteins, our work will provide deeper insight into mechanisms involved in inflammation, diabetes, cancer and other pathologies arising from the misregulation of cellular secretion.

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