TY - JOUR
T1 - Control of ASPP2/53BP2L protein levels by proteasomal degradation modulates p53 apoptotic function
AU - Zhu, Zhiyi
AU - Ramos, Jason
AU - Kampa, Kerstin
AU - Adimoolam, Shanthi
AU - Sirisawad, Mint
AU - Yu, Zhiyong
AU - Chen, Dexi
AU - Naumovski, Louie
AU - Lopez, Charles D.
PY - 2005/10/14
Y1 - 2005/10/14
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M503736200
DO - 10.1074/jbc.M503736200
M3 - Article
C2 - 16091363
AN - SCOPUS:27144456615
SN - 0021-9258
VL - 280
SP - 34473
EP - 34480
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 41
ER -