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Originally published In Press as doi:10.1074/jbc.M801185200 on June 18, 2008

J. Biol. Chem., Vol. 283, Issue 34, 23274-23287, August 22, 2008
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Heterogeneous Nuclear Ribonucleoprotein A1 Regulates Cyclin D1 and c-myc Internal Ribosome Entry Site Function through Akt Signaling*Formula

Oak D. Jo{ddagger}, Jheralyn Martin{ddagger}, Andrew Bernath{ddagger}, Janine Masri{ddagger}, Alan Lichtenstein{ddagger}§, and Joseph Gera{ddagger}§1

From the {ddagger}Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles California, 91343 and the §Department of Medicine, David Geffen School of Medicine, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90048

The translation of the cyclin D1 and c-myc mRNAs occurs via internal ribosome entry site (IRES)-mediated initiation under conditions of reduced eIF-4F complex formation and Akt activity. Here we identify hnRNP A1 as an IRES trans-acting factor that regulates cyclin D1 and c-myc IRES activity, depending on the Akt status of the cell. hnRNP A1 binds both IRESs in vitro and in intact cells and enhances in vitro IRES-dependent reporter expression. Akt regulates this IRES activity by inducing phosphorylation of hnRNP A1 on serine 199. Serine 199-phosphorylated hnRNP A1 binds to the IRESs normally but is unable to support IRES activity in vitro. Reducing expression levels of hnRNP A1 or overexpressing a dominant negative version of the protein markedly inhibits rapamycin-stimulated IRES activity in cells and correlated with redistribution of cyclin D1 and c-myc transcripts from heavy polysomes to monosomes. Importantly, knockdown of hnRNP A1 also renders quiescent Akt-containing cells sensitive to rapamycin-induced G1 arrest. These results support a role for hnRNP A1 in mediating rapamycin-induced alterations of cyclin D1 and c-myc IRES activity in an Akt-dependent manner and provide the first direct link between Akt and the regulation of IRES activity.


Received for publication, February 13, 2008 , and in revised form, June 12, 2008.

* This work was supported, in whole or in part, by National Institutes of Health Grants R01CA111448 (to A. L.) and R01CA109312 (to J. G.). This work was also supported in part by funds from the Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

1 To whom correspondence should be addressed: Dept. of Research and Development, Veterans Affairs-UCLA Medical Center, 16111 Plummer St. (151), Bldg. 1, Rm. C111A, Los Angeles, CA 91343. Tel.: 818-895-9416; Fax: 818-895-9554; E-mail: gera{at}ucla.edu.


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