A novel phosphorylation-deacetylation cascade mediates RAR agonist-induced p21 expression in VSMCs and inhibition of neointima formation

【作者】 温进坤；

【机构】 河北医科大学；

【摘要】 <正>Cell proliferation is coupled with cell cycle progression,and promoted by cyclins and inhibited by cyclin-dependent kinase inhibitors,which is governed by complex combinatorial interactions between multiple transcription factors and their cofactors. The Krtippel-like factor 5(Klf5),retinoic acid receptor a(RARα) and histone deacetylase 2(HDAC2) are several components of such a complex combinatorial network.However,the direct relationship between Klf5,RARαand HDAC2 in the regulation of VSMC proliferation by Am80 remains unknown.Here,we identified that transcriptional induction of p21 by Am80 involves the disruption of transcriptional repression complex formed by Klf5,RARαand HDAC2.HDAC2 is basally hypophosphorylated in resting cells and hyperphosphorylated by CK2αin response to Am80.Hyperphosphorylation of HDAC2,one aspect,promotes its dissociation from RARα,and then the liganded-RARαinteracts with p300 and is acetylated,subsequently increasing the ability of RARαto activate the p21 promoter. Another aspect,hyperphosphorylation of HDAC2 increases its interaction with Klf5 and leads to deacetylation of Klf5,and then deacetylated Klf5 dissociates from the p21 promoter and loses its inhibitory effect on the p21 promoter.These findings indicate that HDAC2 phosphorylation-dependent mechanisms disrupt the transcriptional repression complex formed by HDAC2,RARαand Klf5,providing a novel mechanism by which phosphorylation-deacetylation cascade regulates transcription factor interactions with their cofactors and the activity of transcription factors.更多还原

【Abstract】 Cell proliferation is coupled with cell cycle progression,and promoted by cyclins and inhibited by cyclin-dependent kinase inhibitors,which is governed by complex combinatorial interactions between multiple transcription factors and their cofactors. The Krtippel-like factor 5(Klf5),retinoic acid receptor a(RARα) and histone deacetylase 2(HDAC2) are several components of such a complex combinatorial network.However,the direct relationship between Klf5,RARαand HDAC2 in the regulation of VSMC proliferation by Am80 remains unknown.Here,we identified that transcriptional induction of p21 by Am80 involves the disruption of transcriptional repression complex formed by Klf5,RARαand HDAC2.HDAC2 is basally hypophosphorylated in resting cells and hyperphosphorylated by CK2αin response to Am80.Hyperphosphorylation of HDAC2,one aspect,promotes its dissociation from RARα,and then the liganded-RARαinteracts with p300 and is acetylated,subsequently increasing the ability of RARαto activate the p21 promoter. Another aspect,hyperphosphorylation of HDAC2 increases its interaction with Klf5 and leads to deacetylation of Klf5,and then deacetylated Klf5 dissociates from the p21 promoter and loses its inhibitory effect on the p21 promoter.These findings indicate that HDAC2 phosphorylation-dependent mechanisms disrupt the transcriptional repression complex formed by HDAC2,RARαand Klf5,providing a novel mechanism by which phosphorylation-deacetylation cascade regulates transcription factor interactions with their cofactors and the activity of transcription factors.更多还原