Modulation of Phosducin-Like Protein 3 (PhLP3) Levels Promotes Cytoskeletal Remodelling in a MAPK and RhoA-Dependent Manner 英文参考文献.docVIP

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Modulation of Phosducin-Like Protein 3 (PhLP3) Levels Promotes Cytoskeletal Remodelling in a MAPK and RhoA-Dependent Manner 英文参考文献.doc

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Modulation of Phosducin-Like Protein 3 (PhLP3) Levels Promotes Cytoskeletal Remodelling in a MAPK and RhoA-Dependent Manner 英文参考文献

ModulationofPhosducin-LikeProtein3(PhLP3)Levels PromotesCytoskeletalRemodellinginaMAPKand RhoA-DependentManner NandiniV.L.Hayes,LyneJosse′,C.MarkSmales*,MartinJ.Carden* CentreforMolecularProcessingandSchoolofBiosciences,UniversityofKent,Canterbury,Kent,UnitedKingdom Abstract Background:Phosducin-likeprotein3(PhLP3)formsaternarycomplexwiththeATP-dependentmolecularchaperoneCCT anditsfoldingclienttubulin.InvitrostudiessuggestPhLP3playsaninhibitoryroleinb-tubulinfoldingwhileconverselyin vivo genetic studies suggest PhLP3 is required for the correct folding of b-tubulin. We have a particular interest in the cytoskeleton, its chaperones and their role in determining cellular phenotypes associated with high level recombinant proteinexpressionfrommammaliancellexpressionsystems. Methodology/PrincipalFindings:AsstudiesintoPhLP3functionhavebeenlargelycarriedoutinnonmammaliansystems, weexaminedtheeffectofhumanPhLP3over-expressionandsiRNAsilencingusingasinglemurinesiRNAonbothtubulin andactinsystemsinmammalianChinesehamsterovary(CHO)celllines.Weshowthatover-expressionofPhLP3promotes an imbalance of a and b tubulin subunits, microtubule disassembly and cell death. In contrast, b-actin levels are not obviouslyperturbed.On-the-other-hand,RNAsilencingofPhLP3increasesRhoA-dependentactinfilamentformationand focaladhesionformationandpromotesadramaticelongatedfibroblast-likechangeinmorphology.Thiswasaccompanied by an increase in phosphorylated MAPK which has been associated with promoting focal adhesion assembly and maturation. Transient overexpression of PhLP3 in knockdown experiments rescues cells from the morphological change observedduringPhLP3silencingbutmitosisisperturbed,probablyreflectingatippingbackofthebalanceofPhLP3levels towardstheoverexpressionstate. Conclusions: Our results support the hypothesis that PhLP3 is important for the maintenance of b-tubulin levels in mammalian cells but also that its modulation can promote actin-based cytoskeletal remodelling by a mechanism li