The regulation of the transcription factor p53 in neurite outgrowth and neuron differentiation

• Antragsteller: Professor Dr. Simone Di Giovanni
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2007 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 54575130

• Erstellungsjahr: 2012

Zusammenfassung der Projektergebnisse

Our research during the funding period has contributed to characterize the role of p53 and its posttranslational modifications in neurite outgrowth and axonal regeneration as well as during neural development and differentiation. Specifically, we have shown that: (a) acetylated p53 K320-72-3-82Q is required for neurite outgrowth and axonal regeneration by forming a transcriptional complex with CBP/p300 and P/CAF; (b) p53 drives the expression of a number of neurite outgrowth genes via neurotrophin and RA signaling and overcomes myelin inhibition of neurite outgrowth; (c) p53 regulates neurogenesis and neuronal differentiation via modulation of oxidative stress and independently of its C-terminus acetylation. No major technical or methodological limitations have been encountered during the funding period. The absence of a role for p53 acetylation during neurogenesis was somewhat surprising but underlines how the function of p53 post-translational modifications is very much context dependent, as also stressed in a recent review (Murray-Zmijewski et al., 2008). Stemming from these findings, current research now focuses on determining the role of p53-dependent pathways in axonal regeneration following spinal cord injury and on the further clarification of the molecular mechanisms that regulate p53-dependent neurogenesis.

Projektbezogene Publikationen (Auswahl)

• A p53-CBP/p300 transcription module is required for GAP-43 expression, axon outgrowth and regeneration. Cell Death Differ. 2009 Apr;16(4):543-54. Epub 2008 Dec 5
  Tedeschi A, Nguyen T, Gaub P, Puttagunta R, Di Giovanni S
  
• Molecular targets for axon regeneration: focus on the intrinsic pathways. Expert Opinion on Therapeutic Targets. 2009 Dec;13(12):1387-98
  Di Giovanni S.
  
• NFAT-3 is a transcriptional repressor of the growth associated protein 43 during neuronal maturation. J Biol Chem. 2009 Jul 10;284(28):18816-23. Epub 2009 May 14
  Nguyen J, Linder R, Tedeschi A, Forsberg K, Green A, Wuttke A, Gaub P, Di Giovanni S
  
• The non-apoptotic role of p53 in neuron biology: enlightening the dark side of the moon. EMBO Rep. 2009 Jun;10(6):576-83. Epub 2009 May 8
  Tedeschi A. and Di Giovanni S.
  
• The tumour suppressor p53 transcriptionally regulates cGKI expression during neuronal maturation and is required for cGMP-dependent growth cone collapse. J Neurosci. 2009 Dec 2;29(48):15155-60
  Tedeschi A, Nguyen T, Steele SU, Feil S, Naumann U, Feil R, Di Giovanni S
  
• HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse via CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death Differ. 2010 Sep;17(9):1392-408
  Gaub P, Tedeschi A, Nguyen T, Schmandke A, Puttagunta R, Di Giovanni S
  
• Chromatin Immunoprecipitation from Dorsal Root Ganglia Tissue following Axonal Injury. Journal of Visualized Experiments. 2011 Jul 20;(53)
  Floriddia E, Nguyen T, Di Giovanni S
  
• RA-RARß counteracts myelin-dependent growth cone collapse and inhibition of neurite outgrowth via transcriptional repression of Lingo-1. J Cell Biol. 2011 193,1147-1156
  Puttagunta R, Schmandke A, Floriddia E, Fomin N, Gaub P, Ghyselinck NB, Di Giovanni S