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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.