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Angus M. MacNicol, Ph.D.

Angus M. MacNicol, Ph.D.

Angus M. MacNicol, Ph.D.Title
Professor

PhD
University of London

Research Interests
Regulated mRNA translation is emerging as a key mechanism to control cell cycle progression during development and in the adult organism. Recent evidence has underscored the importance of regulatory elements in the 3’ untranslated region (3’ UTR) in mediating mRNA translational control in a variety of species and cellular processes including neuronal synaptic plasticity, stem cell self renewal and control of vertebrate oocyte maturation. Aberrant mRNA translational regulation may contribute to cognitive dysfunction, birth defects, infertility and tumor stem cell proliferation. The goal of the research in my lab is to understand the role of regulated mRNA translation in the control of cell cycle progression in both physiological and pathological contexts.
The mRNA translational control protein, Musashi, plays a critical role in promoting physiological stem cell self-renewal and has been implicated in the development and progression of neural, colon, breast and hematopoietic cancers. Musashi binds predominantly to a specific sequence within target 3’ UTRs and acts to promote stem cell proliferation by repressing mRNAs encoding inhibitors of cell cycle progression. Despite our knowledge of the role of Musashi in both physiological and disease states, an understanding of the mechanism by which Musashi exerts translational control is lacking.
Our recent findings demonstrate that Musashi can function to activate mRNA translation during vertebrate oocyte maturation and established a critical role for Musashi-mediated mRNA translational activation in control of oocyte meiotic cell cycle progression. This work revealed a new paradigm for understanding the temporal control of maternal mRNA translation, where a regulatory hierarchy of distinct mRNA translational control pathways function sequentially during meiotic cell cycle progression. We have also shown that Musashi can switch from a repressor to an activator of target mRNA translation during mammalian stem cell differentiation. However, the mechanism controlling this crucial functional switch in Musashi activity has not been established.
We have developed a novel biological assay to directly assess Musashi function during oocyte cell cycle progression and are thus uniquely positioned to identify the molecular mechanisms mediating Musashi-dependent mRNA translational control. Using this assay, we have recently found that Musashi requires activating phosphorylation to promote target mRNA translation during oocyte maturation and that this regulatory phosphorylation similarly occurs during mammalian neural stem cell differentiation. We are currently pursuing further characterizations of Musashi function and regulation in oocytes, mammalian stem/progenitor cells and cancer cells.
Elucidation of the molecular events underlying Musashi-dependent mRNA translational control will not only enhance our understanding of germ cell differentiation but may provide valuable insights into the mechanisms governing stem cell fate determination. This in turn, could lead to novel strategies for treating cancers by direct targeting and manipulation of mRNA translational control programs in the tumor stem cell-like compartment, a compartment that is resistant to conventional therapies.

Email: Angus@uams.edu

Address: Dept. of Neurobiology and Developmental Sciences,
and the Winthrop P. Rockefeller Cancer Institute,
University of Arkansas for Medical Sciences,
4301 W. Markham St. Slot 814,
Little Rock, AR 72205

Phone: 501-686-8164

Fax: 501-686-6517

Selected Publications

Charlesworth, A., Wilczynska, A., Thampi, P., Cox, L.L., and MacNicol, A.M. 2006.  Musashi regulates the temporal order of mRNA translation during Xenopus oocyte maturation. EMBO J.25:2792-2801.

Arumugam, K., Wang, Y., Hardy, L.L., MacNicol, M.C. and MacNicol, A.M. 2010.  Enforcing temporal control of maternal mRNA translation during oocyte cell cycle progression.  EMBO J. 29: 387-397.

MacNicol, M.C. and MacNicol A.M. 2010.  Developmental timing of mRNA translation – integration of distinct regulatory elements.  Molecular Reproduction and Development, 77:662-669. [Review]

MacNicol, M.C., Cragle, C.E. and MacNicol, A.M. 2011.  Context-dependent regulation of Musashi-mediated mRNA translation and cell cycle regulation.  Cell Cycle, 10:39-44.

Arumugam, K., MacNicol, M.C., Wang, Y., Cragle, C.E., Tackett, A.J., Hardy, L.L. and MacNicol, A.M. 2012.  Ringo/cyclin-dependent kinase and mitogen-activated protein kinase signaling pathways regulate the activity of the cell fate determinant Musashi to promote cell cycle re-entry in Xenopus oocytes.  J. Biol. Chem. In press

Link to Dr. MacNicol’s PubMed publications