Exposure of normal and tumor-derived cells to TGFbresults in different outcomes,depending on the regulation of key targets.The CDK inhibitor p27^(Kip1) is one of these TGFβ targets and is essential for the TGFβ-indu...Exposure of normal and tumor-derived cells to TGFbresults in different outcomes,depending on the regulation of key targets.The CDK inhibitor p27^(Kip1) is one of these TGFβ targets and is essential for the TGFβ-induced cell cycle arrest.TGFb treatment inhibits p27^(Kip1) degradation and induces its nuclear translocation,through mechanisms that are still unknown.Recent evidences suggest that SUMOylation,a post-translational modification able to modulate the stability and subcellular localization of target proteins,critically modifies members of the TGFβ signaling pathway.Here,we demonstrate that p27^(Kip1) is SUMOylated in response to TGFβ treatment.Using different p27^(Kip1) point mutants,we identified lysine 134(K134)as the residue modified by small ubiquitin-like modifier 1(SUMO1)in response to TGFb treatment.TGFβ-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27^(Kip1).We observed thatSUMOylation regulated p27^(Kip1) binding to CDK2,thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine 187.Importantly,p27^(Kip1) SUMOylation was necessary for proper cell cycle exit following TGFbtreatment.These data indicate thatSUMOylation is a novel regulatory mechanism that modulates p27^(Kip1) function in response to TGFβ stimulation.Given the involvement of TGFb signaling in cancer cell proliferation and invasion,our data may shed light on an important aspect of this pathway during tumor progression.展开更多
基金supported by Associazione Italiana Ricerca sul Cancro(AIRC)IG 12854 to G.B.and AIRC IG 12075 to S.Ch.,by CRO Intramural research grant to G.B.,and by CRO Young Investigator Program to S.L.S.B.is a recipient of AIRC-Marie Curie Outgoing International Fellowship.S.C.is supported by an FUV(Fondazione Umberto Veronesi)fellowship.
文摘Exposure of normal and tumor-derived cells to TGFbresults in different outcomes,depending on the regulation of key targets.The CDK inhibitor p27^(Kip1) is one of these TGFβ targets and is essential for the TGFβ-induced cell cycle arrest.TGFb treatment inhibits p27^(Kip1) degradation and induces its nuclear translocation,through mechanisms that are still unknown.Recent evidences suggest that SUMOylation,a post-translational modification able to modulate the stability and subcellular localization of target proteins,critically modifies members of the TGFβ signaling pathway.Here,we demonstrate that p27^(Kip1) is SUMOylated in response to TGFβ treatment.Using different p27^(Kip1) point mutants,we identified lysine 134(K134)as the residue modified by small ubiquitin-like modifier 1(SUMO1)in response to TGFb treatment.TGFβ-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27^(Kip1).We observed thatSUMOylation regulated p27^(Kip1) binding to CDK2,thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine 187.Importantly,p27^(Kip1) SUMOylation was necessary for proper cell cycle exit following TGFbtreatment.These data indicate thatSUMOylation is a novel regulatory mechanism that modulates p27^(Kip1) function in response to TGFβ stimulation.Given the involvement of TGFb signaling in cancer cell proliferation and invasion,our data may shed light on an important aspect of this pathway during tumor progression.
