Antiproliferative proteins of the BTG/Tob family are degraded by the ubiquitin-proteasome system

Eur J Biochem. 2002 Jul;269(14):3596-604. doi: 10.1046/j.1432-1033.2002.03052.x.


BTG/Tob family proteins, which are characterized by similarities in their N-terminal BTG/Tob homology domains, control cell growth negatively. Among the BTG/Tob family members, BTG2/TIS21/PC3 proteins have been reported to have short lives and to be degraded by the proteasome. However, the mechanisms regulating the stabilities of other BTG/Tob family proteins have not yet been clarified. Here, we report that BTG1, Tob, and Tob2 proteins, as well as BTG2 protein, are degraded by the ubiquitin-proteasome system; the degradation of Tob protein in HeLa cells and the degradation of BTG1, BTG2, Tob and Tob2 proteins transiently expressed in HEK293 cells were inhibited by treatments with proteasome-specific inhibitors. Co-expression of BTG1, BTG2, Tob, or Tob2 protein with ubiquitin in HEK293 cells revealed specific multiubiquitination of each of the four proteins. Although the full-length and N-terminal truncated forms of BTG1, BTG2, Tob, and Tob2 proteins were unstable, the respective C-terminal truncated forms were found to be almost stable, suggesting that the C-terminal regions control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins. In addition, it was found that the respective C-terminal regions confer instability on green fluorescent protein, a normally stable protein. Thus, it can be concluded that the C-terminal regions are necessary and sufficient to control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Division / physiology
  • Cell Line
  • Genes, Tumor Suppressor
  • Green Fluorescent Proteins
  • Half-Life
  • HeLa Cells
  • Humans
  • Immediate-Early Proteins / chemistry
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins*
  • Kidney
  • Luminescent Proteins / chemistry
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Peptide Fragments / metabolism
  • Peptide Hydrolases / metabolism*
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex*
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / metabolism
  • Tumor Suppressor Proteins*
  • Ubiquitin / metabolism*


  • Carrier Proteins
  • Cell Cycle Proteins
  • Immediate-Early Proteins
  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • Neoplasm Proteins
  • Peptide Fragments
  • Protease Inhibitors
  • Recombinant Fusion Proteins
  • TOB1 protein, human
  • TOB2 protein, human
  • Tumor Suppressor Proteins
  • Ubiquitin
  • BTG2 protein, human
  • BTG1 protein, human
  • Green Fluorescent Proteins
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease