Synemin promotes AKT-dependent glioblastoma cell proliferation by antagonizing PP2A.
The intermediate filament protein synemin is present in astrocyte progenitors and glioblastoma cells but not in mature astrocytes. Here we demonstrate a role for synemin in enhancing glioblastoma cell proliferation and clonogenic survival, as synemin RNA interference decreased both behaviors by inducing G1 arrest along with Rb hypophosphorylation and increased ... protein levels of the G1/S inhibitors p21(Cip1) and p27(Kip1). Akt involvement was demonstrated by decreased phosphorylation of its substrate, p21(Cip1), and reduced Akt catalytic activity and phosphorylation at essential activation sites. Synemin silencing, however, did not affect the activities of PDPK1 and mTOR complex 2, which directly phosphorylate Akt activation sites, but instead enhanced the activity of the major regulator of Akt dephosphorylation, protein phosphatase type 2A (PP2A). This was accompanied by changes in PP2A subcellular distribution resulting in increased physical interactions between PP2A and Akt, as shown by proximity ligation assays (PLAs). PLAs and immunoprecipitation experiments further revealed that synemin and PP2A form a protein complex. In addition, treatment of synemin-silenced cells with the PP2A inhibitor cantharidic acid resulted in proliferation and pAkt and pRb levels similar to those of controls. Collectively these results indicate that synemin positively regulates glioblastoma cell proliferation by helping sequester PP2A away from Akt, thereby favoring Akt activation.
Mesh Terms:
Base Sequence, Cantharidin, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, G1 Phase Cell Cycle Checkpoints, Glioblastoma, Humans, Intermediate Filament Proteins, Models, Biological, Multiprotein Complexes, Phosphatidylinositol 3-Kinases, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, RNA Interference, RNA, Small Interfering, Retinoblastoma Protein, Signal Transduction, Transcription Factors
Base Sequence, Cantharidin, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, G1 Phase Cell Cycle Checkpoints, Glioblastoma, Humans, Intermediate Filament Proteins, Models, Biological, Multiprotein Complexes, Phosphatidylinositol 3-Kinases, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, RNA Interference, RNA, Small Interfering, Retinoblastoma Protein, Signal Transduction, Transcription Factors
Mol. Biol. Cell
Date: Apr. 01, 2012
PubMed ID: 22337773
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