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J Biol Chem. 2005 Oct 14;280(41):34473-80. Epub 2005 Aug 9.

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

Author information

1
Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA.

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.

PMID:
16091363
DOI:
10.1074/jbc.M503736200
[Indexed for MEDLINE]
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