Def defines a conserved nucleolar pathway that leads p53 to proteasome-independent degradation

Cell Res. 2013 May;23(5):620-34. doi: 10.1038/cr.2013.16. Epub 2013 Jan 29.


p53 protein turnover through the ubiquitination pathway is a vital mechanism in the regulation of its transcriptional activity; however, little is known about p53 turnover through proteasome-independent pathway(s). The digestive organ expansion factor (Def) protein is essential for the development of digestive organs. In zebrafish, loss of function of def selectively upregulates the expression of p53 response genes, which raises a question as to what is the relationship between Def and p53. We report here that Def is a nucleolar protein and that loss of function of def leads to the upregulation of p53 protein, which surprisingly accumulates in the nucleoli. Our extensive studies have demonstrated that Def can mediate the degradation of p53 protein and that this process is independent of the proteasome pathway, but dependent on the activity of Calpain3, a cysteine protease. Our findings define a novel nucleolar pathway that regulates the turnover function of p53, which will advance our understanding of p53's role in organogenesis and tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calpain / antagonists & inhibitors
  • Calpain / genetics
  • Calpain / metabolism
  • Cell Line
  • Cell Nucleolus / metabolism
  • Embryo, Nonmammalian / physiology
  • G1 Phase
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Mutation
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitination
  • Up-Regulation
  • Zebrafish / metabolism
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Zebrafish Proteins
  • digestive-organ expansion factor, zebrafish
  • Proto-Oncogene Proteins c-mdm2
  • Calpain
  • Proteasome Endopeptidase Complex