Unknown

Dataset Information

0

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


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.

SUBMITTER: Xu K 

PROVIDER: S-EPMC5064830 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Xu K K   Wang L L   Feng W W   Feng Y Y   Shu H-Kg HK  

Oncogene 20160411 44


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  ...[more]

Similar Datasets

| S-EPMC5088286 | biostudies-literature
| S-EPMC4230483 | biostudies-literature
| S-EPMC4773430 | biostudies-literature
| S-EPMC5737533 | biostudies-literature
| S-EPMC3911288 | biostudies-literature
| S-EPMC2658053 | biostudies-literature
| S-EPMC3083221 | biostudies-literature
| S-EPMC6639073 | biostudies-literature
2020-12-31 | GSE145249 | GEO
| S-EPMC5473210 | biostudies-literature