title: The tumor suppressor p53 transcriptionally regulates cGKI expression during neuronal maturation and is required for cGMP-dependent growth cone collapse.
abstract: The cGMP-dependent protein kinase type I (cGKI) has multiple functions including a role in axonal growth and pathfinding of sensory neurons, and counteracts Semaphorin 3A (Sema3A)-induced growth cone collapse. Within the nervous system, however, the transcriptional regulation of cGKI is still obscure. Recently, the transcription factor and tumor suppressor p53 has been reported to promote neurite outgrowth by regulating the gene expression of factors that promote growth cone extension, but specific p53 targets genes that may counteract growth cone collapse have not been identified so far. Here, we show that p53 promotes cGKI expression in neuronal-like PC-12 cells and primary neurons by occupying specific regulatory elements in a chromatin environment during neuronal maturation. Importantly, we demonstrate that p53-dependent expression of cGKI is required for the ability of cGMP to counteract growth cone collapse. Growth cone retraction mediated by Sema3A is overcome by cGMP only in wild-type, but not in p53-null dorsal root ganglia. Reconstitution of p53 levels is sufficient to recover both cGKI expression and the ability of cGMP to counteract growth cone collapse, while cGKI overexpression rescues growth cone collapse in p53-null primary neurons. In conclusion, this study identifies p53 as a transcription factor that regulates the expression of cGKI during neuronal maturation and cGMP-dependent inhibition of growth cone collapse.
authors: Center for Neurology, Laboratory for NeuroRegeneration and Repair, University of Tuebingen, D-72076 Tuebingen, Germany.
authors: Andrea
authors: A
authors: Tedeschi
authors: Tuan
authors: T
authors: Nguyen
authors: Sonya Ulrike
authors: SU
authors: Steele
authors: Susanne
authors: S
authors: Feil
authors: Ulrike
authors: U
authors: Naumann
authors: Robert
authors: R
authors: Feil
authors: Simone
authors: S
authors: Di Giovanni
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation / Q000379:methods; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D040121:Semaphorin-3A / Q000235:genetics; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D040121:Semaphorin-3A; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; C016276:8-bromocyclic GMP; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D006152:Cyclic GMP