NDLI: Phosphomimetic Substitution of Heterogeneous Nuclear Ribonucleoprotein A1 at Serine 199 Abolishes AKT-dependent Internal Ribosome Entry Site-transacting Factor (ITAF) Function via Effects on Strand Annealing and Results in Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitor Sensitivity*

Content Provider	PubMed Central
Author	Martin, Jheralyn Masri, Janine Cloninger, Cheri Holmes, Brent Artinian, Nicholas Funk, Alexander Ruegg, Teresa Anderson, Lauren Bashir, Tariq Bernath, Andrew Lichtenstein, Alan Gera, Joseph
Copyright Year	2011
Abstract	The relative activity of the AKT kinase has been demonstrated to be a major determinant of sensitivity of tumor cells to mammalian target of rapamycin (mTOR) complex 1 inhibitors. Our previous studies have shown that the multifunctional RNA-binding protein heterogeneous nuclear ribonucleoprotein (hnRNP) A1 regulates a salvage pathway facilitating internal ribosome entry site (IRES)-dependent mRNA translation of critical cellular determinants in an AKT-dependent manner following mTOR inhibitor exposure. This pathway functions by stimulating IRES-dependent translation in cells with relatively quiescent AKT, resulting in resistance to rapamycin. However, the pathway is repressed in cells with elevated AKT activity, rendering them sensitive to rapamycin-induced G1 arrest as a result of the inhibition of global eIF-4E-mediated translation. AKT phosphorylation of hnRNP A1 at serine 199 has been demonstrated to inhibit IRES-mediated translation initiation. Here we describe a phosphomimetic mutant of hnRNP A1 (S199E) that is capable of binding both the cyclin D1 and c-MYC IRES RNAs in vitro but lacks nucleic acid annealing activity, resulting in inhibition of IRES function in dicistronic mRNA reporter assays. Utilizing cells in which AKT is conditionally active, we demonstrate that overexpression of this mutant renders quiescent AKT-containing cells sensitive to rapamycin in vitro and in xenografts. We also demonstrate that activated AKT is strongly correlated with elevated Ser(P)199-hnRNP A1 levels in a panel of 22 glioblastomas. These data demonstrate that the phosphorylation status of hnRNP A1 serine 199 regulates the AKT-dependent sensitivity of cells to rapamycin and functionally links IRES-transacting factor annealing activity to cellular responses to mTOR complex 1 inhibition.
Related Links	http://dx.doi.org/10.1074/jbc.m110.205096
Ending Page	16413
Page Count	12
Starting Page	16402
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	18
Volume Number	286
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-05-06
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Phosphomimetic Substitution of Heterogeneous Nuclear Ribonucleoprotein A1 at Serine 199 Abolishes AKT-dependent Internal Ribosome Entry Site-transacting Factor (ITAF) Function via Effects on Strand Annealing and Results in Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitor Sensitivity

Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma

Heterogeneous Nuclear Ribonucleoprotein A1 Regulates Cyclin D1 and c-myc Internal Ribosome Entry Site Function through Akt Signaling

Heterogeneous Nuclear Ribonucleoprotein A1 Regulates Cyclin D1 and c-myc Internal Ribosome Entry Site Function through Akt Signaling* S⃞

Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling. VOLUME 283 (2008) PAGES 23274-23287

Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling.

An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1

Akt-dependent Activation of mTORC1 Complex Involves Phosphorylation of mTOR (Mammalian Target of Rapamycin) by IκB Kinase α (IKKα)

An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1* S⃞

Phosphomimetic Substitution of Heterogeneous Nuclear Ribonucleoprotein A1 at Serine 199 Abolishes AKT-dependent Internal Ribosome Entry Site-transacting Factor (ITAF) Function via Effects on Strand Annealing and Results in Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitor Sensitivity*

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Phosphomimetic Substitution of Heterogeneous Nuclear Ribonucleoprotein A1 at Serine 199 Abolishes AKT-dependent Internal Ribosome Entry Site-transacting Factor (ITAF) Function via Effects on Strand Annealing and Results in Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitor Sensitivity

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Phosphomimetic Substitution of Heterogeneous Nuclear Ribonucleoprotein A1 at Serine 199 Abolishes AKT-dependent Internal Ribosome Entry Site-transacting Factor (ITAF) Function via Effects on Strand Annealing and Results in Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitor Sensitivity*