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 journalArticle

    30 Scopus citations

    Abstract

    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
    Volume280
    Issue number41
    DOIs
    StatePublished - Oct 14 2005

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Fingerprint Dive into the research topics of 'Control of ASPP2/<sup>53BP2L</sup> protein levels by proteasomal degradation modulates p53 apoptotic function'. Together they form a unique fingerprint.

  • Cite this

    Zhu, Z., Ramos, J., Kampa, K., Adimoolam, S., Sirisawad, M., Yu, Z., Chen, D., Naumovski, L., & Lopez, C. D. (2005). Control of ASPP2/53BP2L protein levels by proteasomal degradation modulates p53 apoptotic function. Journal of Biological Chemistry, 280(41), 34473-34480. https://doi.org/10.1074/jbc.M503736200