A New Role of c-FLIPL in Modulation of Wnt Pathway by Association with TIP49

【作者】 张晶； 刘万； 华子春；

【机构】 Nanjing University；

【摘要】 Death receptors belonging to the tumor necrosis factor receptor family(e.g.,Fas/CD95,TNFR1,TRAIL/DR5)play an important role in apoptosis.The cellular FLICE-inhibitory protein(c-FLIP)is a key inhibitory protein in the extrinsic apoptotic pathway by death receptors.Two main forms of c-FLIP have been well characterized:c-FLIP short form(c-FLIPS)andlong form(c-FLIPL).c-FLIPL is homologous to caspase-8,consisting of two DEDs and acatalytically inactive caspaselike domain.In addition to its apoptotic inhibition,c-FLIPLalso activates several cytoprotective signaling pathways involved in regulating cell survival,proliferation,and carcinogenesis.Dysregulation of c-FLIP expression has been associatedwith diseases such as cancer and autoimmune diseases.Recently,c-FLIPL has been shownto shuttle between the nucleus and the cytoplasm reported by our group and others.CFLIPLcan translocate into the nucleus and modulate the Wnt signaling.Nuclear function ofc-FLIPL is mostly unknown.Here we find a novel c-FLIPL associated nuclear protein TIP49,which belongs tothe AAA+family of ATPase involved in chromatin-remodeling and transcriptionalregulation.TIP49 has been identified to interact with TBP,E2F1,oncogenes cmycandβ-catenin.Considering nuclear c-FLIPL previously reported in the modulation ofWnt signaling,we speculate on a new role for c-FLIPL in the transcriptional regulation viainteraction with TIP49.They co-localizate in the nucleus and regulate the transcriptionalactivity ofβ-catenin.Using ChIP methods,c-FLIPL was found to interact with sequences ofβ-catenin/TCF binding site in the promoter region of human ITF-2 gene.The ability of c-FLIPL inβ-catenin/TCF complexes was linked to increased the recruitment of TIP49.Downregulationof TIP49 with siRNA can suppress c-FLIPL-driven Wnt activation,and then weakenc-FLIPL-mediated cell proliferation.These results suggest a new role for nuclear c-FLIPLin modulation of Wnt pathway by association with TIP49.更多还原

【Abstract】 Death receptors belonging to the tumor necrosis factor receptor family(e.g.,Fas/CD95,TNFR1,TRAIL/DR5)play an important role in apoptosis.The cellular FLICE-inhibitory protein(c-FLIP)is a key inhibitory protein in the extrinsic apoptotic pathway by death receptors.Two main forms of c-FLIP have been well characterized:c-FLIP short form(c-FLIPS)andlong form(c-FLIPL).c-FLIPL is homologous to caspase-8,consisting of two DEDs and acatalytically inactive caspaselike domain.In addition to its apoptotic inhibition,c-FLIPLalso activates several cytoprotective signaling pathways involved in regulating cell survival,proliferation,and carcinogenesis.Dysregulation of c-FLIP expression has been associatedwith diseases such as cancer and autoimmune diseases.Recently,c-FLIPL has been shownto shuttle between the nucleus and the cytoplasm reported by our group and others.CFLIPLcan translocate into the nucleus and modulate the Wnt signaling.Nuclear function ofc-FLIPL is mostly unknown.Here we find a novel c-FLIPL associated nuclear protein TIP49,which belongs tothe AAA+family of ATPase involved in chromatin-remodeling and transcriptionalregulation.TIP49 has been identified to interact with TBP,E2F1,oncogenes cmycandβ-catenin.Considering nuclear c-FLIPL previously reported in the modulation ofWnt signaling,we speculate on a new role for c-FLIPL in the transcriptional regulation viainteraction with TIP49.They co-localizate in the nucleus and regulate the transcriptionalactivity ofβ-catenin.Using ChIP methods,c-FLIPL was found to interact with sequences ofβ-catenin/TCF binding site in the promoter region of human ITF-2 gene.The ability of c-FLIPL inβ-catenin/TCF complexes was linked to increased the recruitment of TIP49.Downregulationof TIP49 with siRNA can suppress c-FLIPL-driven Wnt activation,and then weakenc-FLIPL-mediated cell proliferation.These results suggest a new role for nuclear c-FLIPLin modulation of Wnt pathway by association with TIP49.更多还原