Control of ASPP2/(53BP2L) protein levels by proteasomal degradation modulates p53 apoptotic function

J Biol Chem. 2005 Oct 14;280(41):34473-80. doi: 10.1074/jbc.M503736200. Epub 2005 Aug 9.

Abstract

The p53 pathway is a central mediator of the apoptotic response. ASPP2/(53BP2L) (apoptosis-stimulating protein of p53 2, also known as 53BP2L) enhances apoptosis through selective stimulation of p53 transactivation of proapoptotic target genes. Although the Rb/E2F pathway regulates ASPP2/(53BP2L) transcription, the complex mechanisms controlling ASPP2/(53BP2L) levels and function remain unknown. We now report that proteasomal degradation modulates ASPP2/(53BP2L) protein levels and apoptotic function. Treatment of cells with proteasomal inhibitors, including the clinically utilized proteasomal inhibitor bortezomib, increases ASPP2/(53BP2L) protein but not RNA levels. Likewise, anthracycline-based chemotherapy, which has multiple mechanisms of action, including proteasomal inhibition, increases ASPP2/(53BP2L) protein but not RNA levels. Proteasomal inhibition or anthracycline treatment increases ASPP2/(53BP2L) protein stability and half-life. Furthermore, the central region of the ASPP2/(53BP2L) protein is ubiquitinated as would be expected for a proteasomal substrate. More importantly, small interfering RNA knockdown of ASPP2/(53BP2L) levels attenuated bortezomib-induced apoptosis, and this effect was greater in wild-type p53 cells. Because elevated levels of ASPP2/(53BP2L) are proapoptotic, these results described an important new molecular mechanism that modulates the p53-ASPP2/(53BP2L) apoptotic pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anthracyclines / pharmacology
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Blotting, Northern
  • Blotting, Western
  • Boronic Acids / pharmacology
  • Bortezomib
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / physiology*
  • Cell Line
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • E2F Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Proteasome Endopeptidase Complex / metabolism*
  • Pyrazines / pharmacology
  • RNA / metabolism
  • RNA Interference
  • RNA Processing, Post-Transcriptional
  • RNA, Small Interfering / metabolism
  • Retinoblastoma Protein / metabolism
  • Time Factors
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology*
  • Ubiquitin / metabolism

Substances

  • Anthracyclines
  • Apoptosis Regulatory Proteins
  • Boronic Acids
  • Carrier Proteins
  • E2F Transcription Factors
  • Pyrazines
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • TP53BP2 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • RNA
  • Bortezomib
  • Proteasome Endopeptidase Complex