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GENES & DEVELOPMENT 18:48-61, 2004
©2004 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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RESEARCH PAPER

Progesterone and insulin stimulation of CPEB-dependent polyadenylation is regulated by Aurora A and glycogen synthase kinase-3

Madathia Sarkissian, Raul Mendez1 and Joel D. Richter2

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

Progesterone stimulation of Xenopus oocyte maturation requires the cytoplasmic polyadenylation-induced translation of mos and cyclin B mRNAs. One cis element that drives polyadenylation is the CPE, which is bound by the protein CPEB. Polyadenylation is stimulated by Aurora A (Eg2)-catalyzed CPEB serine 174 phosphorylation, which occurs soon after oocytes are exposed to progesterone. Here, we show that insulin also stimulates Aurora A-catalyzed CPEB S174 phosphorylation, cytoplasmic polyadenylation, translation, and oocyte maturation. However, these insulin-induced events are uniquely controlled by PI3 kinase and PKC-{zeta}, which act upstream of Aurora A. The intersection of the progesterone and insulin signaling pathways occurs at glycogen synthase kinase 3 (GSK-3), which regulates the activity of Aurora A. GSK-3 and Aurora A interact in vivo, and overexpressed GSK-3 inhibits Aurora A-catalyzed CPEB phosphorylation. In vitro, GSK-3 phosphorylates Aurora A on S290/291, the result of which is an autophosphorylation of serine 349. GSK-3 phosphorylated Aurora A, or Aurora A proteins with S290/291D or S349D mutations, have reduced or no capacity to phosphorylate CPEB. Conversely, Aurora A proteins with S290/291A or S349A mutations are constitutively active. These results suggest that the progesterone and insulin stimulate maturation by inhibiting GSK-3, which allows Aurora A activation and CPEB-mediated translation.

[Keywords: Insulin; GSK-3; Xenopus oocytes; Aurora A; cytoplasmic polyadenylation; CPEB]

Received July 23, 2003; revised version accepted November 19, 2003.


Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1136004.

1 Present address: Center for Genomic Regulation, Passeig Maritim 37-49, 08003 Barcelona, Spain.

2 Corresponding author.

E-MAIL Joel.Richter{at}umassmed.edu; FAX (508) 856-4289.


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