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

Zhiyi Zhu, Jason Ramos, Kerstin Kampa, Shanthi Adimoolam, Mint Sirisawad, Zhiyong Yu, Dexi Chen, Louie Naumovski, Charles D. Lopez

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


The p53 pathway is a central mediator of the apoptotic response. ASPP2/53BP2L (apoptosis-stimulating grotein 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.

Original languageEnglish (US)
Pages (from-to)34473-34480
Number of pages8
JournalJournal of Biological Chemistry
Issue number41
StatePublished - Oct 14 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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