Control of ASPP2/(53BP2L) protein levels by proteasomal degradation modulates p53 apoptotic function.
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.
Zhu
Zhiyi
Z
Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA.
Ramos
Jason
J
Kampa
Kerstin
K
Adimoolam
Shanthi
S
Sirisawad
Mint
M
Yu
Zhiyong
Z
Chen
Dexi
D
Naumovski
Louie
L
Lopez
Charles D
CD
D018943:Anthracyclines / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015152:Blotting, Northern; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D050684:E2F Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
D018943:Anthracyclines; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; D002352:Carrier Proteins; D050684:E2F Transcription Factors; D011719:Pyrazines; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C090468:TP53BP2 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D012313:RNA; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex