title: Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA.
abstract: Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial early event in neuroblastoma pathogenesis is arrested differentiation of neuroblasts at various stages. Treatment of neuroblastoma with TPA and PDGF-BB leads to terminal differentiation of neuroblastoma cells. However, the signaling pathways that are involved in this process remain largely unknown. Here, we report that inhibition of endogenous FOXO proteins attenuated TPA/PDGF-BB mediated differentiation of neuroblastoma cells. Activated FOXO transcription factors acted on PDGFRA promoter to direct its basal mRNA expression as well as its induction upon serum deprivation. Depletion of endogenous PDGFRA in neuroblastoma cells significantly diminished neurite formation and extension under TPA/PDGF-BB treatment. Furthermore, ectopic expression of PDGFRA abolished the blockage of neuroblastoma differentiation by FOXOs inhibition. These findings define the FOXO-PDGFRA axis as crucial mechanistic components that govern TPA-induced neuroblastoma differentiation.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences,  Xiamen University, Xiamen, Fujian 361005,  China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mei
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yiru
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Huihui
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
authors.forename: Han
authors.initials: H
authors.lastname: You
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D013755:Tetradecanoylphorbol Acetate