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Author Notes:

Correspondence: Dr H-KG Shu, Department of Radiation Oncology and the Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Suite CT-104, Atlanta, GA 30322, USA. E-mail: hgshu@emory.edu

We thank Dr. Walter Curran for providing departmental funding support and Dr. Chi-Ming Chang for helpful discussion in regards to this project.

The authors declare no conflict of interest.

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Research Funding:

Financial support: This work was supported in part by a grant (to H.G.S.) from the Southeast Brain Tumor Foundation and a Cancer Center grant from the National Cancer Institute (P30-CA138292).

Phosphatidylinositol-3 kinase-dependent translational regulation of Id1 involves the PPM1G phosphatase

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Journal Title:

Oncogene

Volume:

Volume 35, Number 44

Publisher:

, Pages 5807-5816

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Id1 is a helix-loop-helix transcriptional modulator that increases the aggressiveness of malignant glial neoplasms. Since most glioblastomas (GBMs) show increased phosphatidylinositol-3 kinase (PI-3K) signaling, we sought to determine whether this pathway regulates Id1 expression. Higher basal Id1 expression correlates with dysregulated PI-3K signaling in multiple established GBM cell lines. Further characterization of PI-3K-dependent Id1 regulation reveals that chemical or genetic inhibition of PI-3K signaling reduces Id1 protein but not mRNA expression. Overall, PI-3K signaling appears to enhance Id1 translation with no significant effect on its stability. PI-3K signaling is known to regulate protein translation through mTORC1-dependent phosphorylation of 4E-BP1, which reduces its association with and inhibition of the translation initiation factor eIF4E. Interestingly, while inhibition of PI-3K and AKT lowers 4E-BP1 phosphorylation and expression of Id1 in all cases, inhibition of TORC1 with rapamycin does not consistently have a similar effect, suggesting an alternative mechanism for PI-3K-dependent regulation of Id1 translation. We now identify a potential role for the serine–threonine phosphatase PPM1G in translational regulation of Id1 protein expression. PPM1G knockdown by siRNA increase both 4E-BP1 phosphorylation and Id1 expression and PPM1G and 4E-BP1 co-associates in GBM cells. Furthermore, PPM1G is a phosphoprotein and this phosphorylation appears to be regulated by PI-3K activity. Finally, PI-3K inhibition increases PPM1G activity when assessed by an in vitro phosphatase assay. Our findings provide the first evidence that the PI-3K/AKT signaling pathway modulates PPM1G activity resulting in a shift in the balance between hyper- and hypo-phosphorylated 4E-BP1 and translational regulation of Id1 expression.Oncogene advance online publication, 11 April 2016; doi:10.1038/onc.2016.115.

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© 2016 Macmillan Publishers Limited

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