The PIDDosome activates p53 in response to supernumerary centrosomes

被引：158
作者：
Fava, Luca L. [1 ]
Schuler, Fabian [1 ]
Sladky, Valentina [1 ]
Haschka, Manuel D. [1 ]
Soratroi, Claudia [1 ]
Eiterer, Lisa [1 ]
Demetz, Egon [2 ]
Weiss, Guenter [2 ]
Geley, Stephan [3 ]
Nigg, Erich A. [4 ]
Villunger, Andreas [1 ,5 ]
机构：
[1] Med Univ Innsbruck, Divis Dev Immunol, Bioctr, A-6020 Innsbruck, Austria
[2] Med Univ Innsbruck, Dept Internal Med 6, Infect Dis Immunol Rheumatol Pneumol, A-6020 Innsbruck, Austria
[3] Med Univ Innsbruck, Div Mol Pathophysiol, Bioctr, A-6020 Innsbruck, Austria
[4] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland
[5] Tyrolean Canc Res Inst, A-6020 Innsbruck, Austria
来源：
GENES & DEVELOPMENT | 2017年 / 31卷 / 01期
基金：
奥地利科学基金会; 瑞士国家科学基金会;
关键词：
cell division; centrosome; cytokinesis failure; p53; DNA-DAMAGE; CHROMOSOMAL INSTABILITY; P53-INDUCED PROTEIN; MITOTIC CATASTROPHE; CASPASE-2; CANCER; CELLS; DEATH; DUPLICATION; SUPPRESSION;
D O I：
10.1101/gad.289728.116
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDD osome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.
引用
收藏
页码：34 / 45
页数：12
相关论文
共 58 条
  • [1] A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization
    Aylon, Yael
    Michael, Dan
    Shmueli, Ayelet
    Yabuta, Norikazu
    Nojima, Hiroshi
    Oren, Moshe
    [J]. GENES & DEVELOPMENT, 2006, 20 (19) : 2687 - 2700
  • [2] The biochemical mechanism of caspase-2 activation
    Baliga, BC
    Read, SH
    Kumar, S
    [J]. CELL DEATH AND DIFFERENTIATION, 2004, 11 (11) : 1234 - 1241
  • [3] P53-induced protein with a death domain (PIDD): master of puppets?
    Bock, F. J.
    Peintner, L.
    Tanzer, M.
    Manzl, C.
    Villunger, A.
    [J]. ONCOGENE, 2012, 31 (45) : 4733 - 4739
  • [4] Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy
    Castedo, M
    Perfettini, JL
    Roumier, T
    Valent, A
    Raslova, H
    Yakushijin, K
    Horne, D
    Feunteun, J
    Lenoir, G
    Medema, R
    Vainchenker, W
    Kroemer, G
    [J]. ONCOGENE, 2004, 23 (25) : 4362 - 4370
  • [5] Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
    Coelho, Paula A.
    Bury, Leah
    Shahbazi, Marta N.
    Liakath-Ali, Kifayathullah
    Tate, Peri H.
    Wormald, Sam
    Hindley, Christopher J.
    Huch, Meritxell
    Archer, Joy
    Skarnes, William C.
    Zernicka-Goetz, Magdalena
    Glover, David M.
    [J]. OPEN BIOLOGY, 2015, 5 (12):
  • [6] Centrosome function and assembly in animal cells
    Conduit, Paul T.
    Wainman, Alan
    Raff, Jordan W.
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2015, 16 (10) : 611 - 624
  • [7] DNA breaks and chromosome pulverization from errors in mitosis
    Crasta, Karen
    Ganem, Neil J.
    Dagher, Regina
    Lantermann, Alexandra B.
    Ivanova, Elena V.
    Pan, Yunfeng
    Nezi, Luigi
    Protopopov, Alexei
    Chowdhury, Dipanjan
    Pellman, David
    [J]. NATURE, 2012, 482 (7383) : 53 - U70
  • [8] p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress
    Cuenin, S.
    Tinel, A.
    Janssens, S.
    Tschopp, J.
    [J]. ONCOGENE, 2008, 27 (03) : 387 - 396
  • [9] The Causes and Consequences of Polyploidy in Normal Development and Cancer
    Davoli, Teresa
    de Lange, Titia
    [J]. ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, VOL 27, 2011, 27 : 585 - 610
  • [10] Spatial and temporal diversity in genomic instability processes defines lung cancer evolution
    de Bruin, Elza C.
    McGranahan, Nicholas
    Mitter, Richard
    Salm, Max
    Wedge, David C.
    Yates, Lucy
    Jamal-Hanjani, Mariam
    Shafi, Seema
    Murugaesu, Nirupa
    Rowan, Andrew J.
    Groenroos, Eva
    Muhammad, Madiha A.
    Horswell, Stuart
    Gerlinger, Marco
    Varela, Ignacio
    Jones, David
    Marshall, John
    Voet, Thierry
    Van Loo, Peter
    Rassl, Doris M.
    Rintoul, Robert C.
    Janes, Sam M.
    Lee, Siow-Ming
    Forster, Martin
    Ahmad, Tanya
    Lawrence, David
    Falzon, Mary
    Capitanio, Arrigo
    Harkins, Timothy T.
    Lee, Clarence C.
    Tom, Warren
    Teefe, Enock
    Chen, Shann-Ching
    Begum, Sharmin
    Rabinowitz, Adam
    Phillimore, Benjamin
    Spencer-Dene, Bradley
    Stamp, Gordon
    Szallasi, Zoltan
    Matthews, Nik
    Stewart, Aengus
    Campbell, Peter
    Swanton, Charles
    [J]. SCIENCE, 2014, 346 (6206) : 251 - 256
123456