BC-Box Motif-Mediated Neuronal Differentiation of Somatic Stem Cells

Int J Mol Sci. 2018 Feb 5;19(2):466. doi: 10.3390/ijms19020466.


Von Hippel-Lindau tumor suppressor protein (pVHL) functions to induce neuronal differentiation of neural stem/progenitor cells (NSCs) and skin-derived precursors (SKPs). Here we identified a neuronal differentiation domain (NDD) in pVHL. Neuronal differentiation of SKPs was induced by intracellular delivery of a peptide composed of the amino-acid sequences encoded by the NDD. Neuronal differentiation mediated by the NDD was caused by the binding between it and elongin C followed by Janus kinase-2 (JAK2) ubiquitination of JAK2 and inhibition of the JAK2/the signal transducer and activator of transcription-3(STAT)3 pathway. The NDD in pVHL contained the BC-box motif ((A,P,S,T)LXXX (A,C) XXX(A,I,L,V)) corresponding to the binding site of elongin C. Therefore, we proposed that other BC-box proteins might also contain an NDD; and subsequently also identified in them an NDD containing the amino-acid sequence encoded by the BC-box motif in BC-box proteins. Furthermore, we showed that different NDD peptide-delivered cells differentiated into different kinds of neuron-like cells. That is, dopaminergic neuron-like cells, cholinergic neuron-like cells, GABAnergic neuron-like cells or rhodopsin-positive neuron-like cells were induced by different NDD peptides. These novel findings might contribute to the development of a new method for promoting neuronal differentiation and shed further light on the mechanism of neuronal differentiation of somatic stem cells.

Keywords: BC-box motif; BC-box protein; neuronal differentiation; skin-derived precursors.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Animals, Newborn
  • Cell Differentiation
  • Cholinergic Neurons / cytology
  • Cholinergic Neurons / drug effects*
  • Cholinergic Neurons / metabolism
  • Dermis / cytology
  • Dermis / drug effects
  • Dermis / metabolism
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Elongin / genetics
  • Elongin / metabolism
  • GABAergic Neurons / cytology
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • Gene Expression Regulation
  • Injections, Intraventricular
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • Protein Binding
  • Protein Domains
  • Rats
  • Rats, Wistar
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Stem Cells / cytology
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • Eloc protein, rat
  • Elongin
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Jak2 protein, rat
  • Janus Kinase 2