RARRES1 regulation of alpha-tubulin tyrosination, cytokinesis and vertebrate embryonic development
Hall, Michael David.
Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. Vitamins A and D are critical for embryonic development and mineral ion homeostasis and have proven effective as chemotherapeutic and chemointerventive agents in cancer through their differentiation-inducing and anti-proliferative properties. However, little is known about the potential commonly regulated downstream genes which exert these effects. Here we report that the largely unstudied RARRES1, a putative tumor suppressor, is one gene commonly regulated by both vitamin A and D in cancer cells. The RARRES1 paralogue, latexin, is a putative carboxypeptidase inhibitor shown to be involved in the regulation of the haematopoietic stem cell population in mice. Our findings indicate that RARRES1 and latexin are the products of a gene duplication event, and that RARRES1 is the ancestral gene in this family. RARRES1 expression is progressively lost in the pathology of prostate cancer and in highly aggressive cancer cells vitamins A and D fail to induce its expression. RARRES1 interacts with and regulates the activity of a novel cytosolic carboxypeptidase (AGBL2) that detyrosinates the C-terminal EEY-regions of alpha-tubulin and EB1, a protein involved in microtubule stability. RARRES1 is a Golgi-associated transmembrane protein that is transported to the cleavage furrow and midbody in dividing cells. Depletion of RARRES1 increased the incidence of multinucleated cells and impedes cell motility. Further, RARRES1 depletion alters the expression of genes involved in normal prostate epithelial biology. Zebrafish Rarres1 mRNA is maternally deposited and robustly expressed in the periventricular regions of the developing brain, and in the intermediate cell mass, sites of neuronal and haematopoietic lineage specification respectively. Knockdown of Rarres1 caused defects in brain development and somitogenesis and dramatically alters the viability of wild-type zebrafish embryos. This data points to a role for RARRES1, AGBL2, EB1 and the microtubule tyrosination cycle in cytokinesis, tumorigenesis and stem cell lineage specification and identify a novel area for intervention.
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