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Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells

Authors
Park, SH; Park, TJ; Lim, IK
Citation
Experimental cell research, 317(7):941-954, 2011
Journal Title
Experimental cell research
ISSN
0014-48271090-2422
Abstract
We have previously reported that G-actin accumulation in nuclei is a universal phenomenon of cellular senescence. By employing primary culture of human diploid fibroblast (HDF) and stress-induced premature senescence (SIPS), we explored whether the failure of actin export to cytoplasm is responsible for actin accumulation in nuclei of senescent cells. Expression of exportin 6 (Exp6) and small G-protein, Ran, was significantly reduced in the replicative senescence, but not yet in SIPS, whereas nuclear import of actin by cofilin was already increased in SIPS. After treatment of young HDF cells with H(2)O(2), rapid reduction of nuclear RanGTP was observed along with cytoplasmic increase of RanGDP. Furthermore, significantly reduced interaction of Exp6 with RanGTP was found by GST-Exp6 pull-down analysis. Failure of RanGTP restoration was accompanied with inhibition of ATP synthesis and NTF2 sequestration in the nuclei along with accordant change of senescence morphology. Indeed, knockdown of Exp6 expression significantly increased actin molecule in the nuclei of young HDF cells. Therefore, actin accumulation in nuclei of senescent cells is most likely due to the failure of RanGTP restoration with ATP deficiency and NTF2 accumulation in nuclei, which result in the decrease of actin export via Exp6 inactivation, in addition to actin import by cofilin activation.
MeSH terms
Actin Depolymerizing Factors/metabolismActins/*metabolismAdenosine Triphosphate/metabolismCell Aging/drug effects/*physiologyCell Nucleus/*metabolismCells, CulturedFibroblasts/cytology/drug effects/physiologyHumansHydrogen Peroxide/pharmacologyKaryopherins/genetics/*metabolismNucleocytoplasmic Transport Proteins/genetics/*metabolismOxidants/pharmacologyPregnancy Proteins/genetics/*metabolismRecombinant Fusion Proteins/genetics/metabolismran GTP-Binding Protein/genetics/*metabolism
DOI
10.1016/j.yexcr.2010.12.023
PMID
21195711
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
박, 태준임, 인경
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