PEPD is a pivotal regulator of p53 tumor suppressor

被引:29
作者
Yang, Lu [1 ]
Li, Yun [1 ,2 ]
Bhattacharya, Arup [1 ]
Zhang, Yuesheng [1 ,3 ]
机构
[1] Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA
[2] Roswell Pk Canc Inst, Dept Urol, Buffalo, NY 14263 USA
[3] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA
关键词
PROTEIN-PROTEIN INTERACTION; GROWTH-FACTOR RECEPTOR; PROLINE-RICH DOMAIN; PROLIDASE DEFICIENCY; SH3; DOMAIN; EXPRESSION; APOPTOSIS; ENZYME; TRANSACTIVATION; CHEMOTHERAPY;
D O I
10.1038/s41467-017-02097-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H2O2 each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for the stress response, but this also renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases.
引用
收藏
页数:15
相关论文
共 59 条
[41]   UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug [J].
Oneyama, C ;
Nakano, H ;
Sharma, SV .
ONCOGENE, 2002, 21 (13) :2037-2050
[42]   HUMAN BLADDER-CARCINOMA CELL-LINES AS INDICATORS OF ONCOGENIC CHANGE RELEVANT TO UROTHELIAL NEOPLASTIC PROGRESSION [J].
RIEGER, KM ;
LITTLE, AR ;
SWART, JM ;
KASTRINAKIS, WV ;
FITZGERALD, JM ;
HESS, DT ;
LIBERTINO, JA ;
SUMMERHAYES, IC .
BRITISH JOURNAL OF CANCER, 1995, 72 (03) :683-690
[43]   Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation [J].
Rodriguez, MS ;
Desterro, JMP ;
Lain, S ;
Lane, DP ;
Hay, RT .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (22) :8458-8467
[44]   The immortalized UROtsa cell line as a potential cell culture model of human urothelium [J].
Rossi, MR ;
Masters, JRW ;
Park, S ;
Todd, JH ;
Garrett, SH ;
Sens, MA ;
Somji, S ;
Nath, J ;
Sens, DA .
ENVIRONMENTAL HEALTH PERSPECTIVES, 2001, 109 (08) :801-808
[45]  
Sharma Arishya, 2012, Methods Mol Biol, V920, P613, DOI 10.1007/978-1-61779-998-3_40
[46]   WW domains [J].
Staub, O ;
Rotin, D .
STRUCTURE, 1996, 4 (05) :495-499
[47]   Prolidase-dependent regulation of collagen biosynthesis [J].
Surazynski, A. ;
Miltyk, W. ;
Palka, J. ;
Phang, J. M. .
AMINO ACIDS, 2008, 35 (04) :731-738
[48]   Extracellular matrix and HIF-1 signaling: The role of prolidase [J].
Surazynski, Arkadiusz ;
Donald, Steven P. ;
Cooper, Sandra K. ;
Whiteside, Martin A. ;
Salnikow, Konstantin ;
Liu, Yongmin ;
Phang, James M. .
INTERNATIONAL JOURNAL OF CANCER, 2008, 122 (06) :1435-1440
[49]   Ubiquitin-independent p53 proteasomal degradation [J].
Tsvetkov, P. ;
Reuven, N. ;
Shaul, Y. .
CELL DEATH AND DIFFERENTIATION, 2010, 17 (01) :103-108
[50]   p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis [J].
Vaseva, Angelina V. ;
Marchenko, Natalie D. ;
Ji, Kyungmin ;
Tsirka, Stella E. ;
Holzmann, Sonja ;
Moll, Ute M. .
CELL, 2012, 149 (07) :1536-1548