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