Mad1 destabilizes p53 by preventing PML from sequestering MDM2.
Animals
Breast Neoplasms
/ genetics
Cell Cycle Proteins
/ genetics
Cells, Cultured
DNA Damage
Escherichia coli
/ genetics
Female
HEK293 Cells
HeLa Cells
Humans
M Phase Cell Cycle Checkpoints
/ genetics
Mice, Nude
Nuclear Proteins
/ genetics
Promyelocytic Leukemia Protein
/ metabolism
Protein Domains
Proto-Oncogene Proteins c-mdm2
/ metabolism
Sumoylation
Tumor Suppressor Protein p53
/ metabolism
Up-Regulation
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 04 2019
04 04 2019
Historique:
received:
15
08
2018
accepted:
12
03
2019
entrez:
6
4
2019
pubmed:
6
4
2019
medline:
2
5
2019
Statut:
epublish
Résumé
Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the mitotic checkpoint. However, interphase roles of Mad1 that do not impact mitotic checkpoint function remain largely uncharacterized. Here we show that upregulation of Mad1, which is common in human breast cancer, prevents stress-induced stabilization of the tumor suppressor p53 in multiple cell types. Upregulated Mad1 localizes to ProMyelocytic Leukemia (PML) nuclear bodies in breast cancer and cultured cells. The C-terminus of Mad1 directly interacts with PML, and this interaction is enhanced by sumoylation. PML stabilizes p53 by sequestering MDM2, an E3 ubiquitin ligase that targets p53 for degradation, to the nucleolus. Upregulated Mad1 displaces MDM2 from PML, freeing it to ubiquitinate p53. Upregulation of Mad1 accelerates growth of orthotopic mammary tumors, which show decreased levels of p53 and its downstream effector p21. These results demonstrate an unexpected interphase role for Mad1 in tumor promotion via p53 destabilization.
Identifiants
pubmed: 30948704
doi: 10.1038/s41467-019-09471-9
pii: 10.1038/s41467-019-09471-9
pmc: PMC6449396
doi:
Substances chimiques
Cell Cycle Proteins
0
MAD1L1 protein, human
0
Nuclear Proteins
0
Promyelocytic Leukemia Protein
0
Tumor Suppressor Protein p53
0
PML protein, human
143220-95-5
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1540Subventions
Organisme : NCI NIH HHS
ID : P30 CA014520
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM088151
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM110567
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009135
Pays : United States
Références
Mol Cell. 2008 Mar 28;29(6):729-41
pubmed: 18374647
Biochem Biophys Res Commun. 1999 Apr 13;257(2):589-95
pubmed: 10198256
J Cell Biochem. 2001 Apr 2-27;82(1):78-88
pubmed: 11400165
Front Biosci (Landmark Ed). 2009 Jan 01;14:1325-36
pubmed: 19273133
Nature. 1997 May 15;387(6630):299-303
pubmed: 9153396
Nat Cell Biol. 2004 Jul;6(7):665-72
pubmed: 15195100
Nat Cell Biol. 2008 May;10(5):538-46
pubmed: 18408734
Curr Biol. 2005 Feb 8;15(3):214-25
pubmed: 15694304
J Struct Funct Genomics. 2015 Dec;16(3-4):101-11
pubmed: 26573864
Mol Cell. 2014 Jul 3;55(1):59-72
pubmed: 24910099
Cell. 2003 Feb 21;112(4):407-21
pubmed: 12600307
Mol Cell. 2018 May 3;70(3):395-407.e4
pubmed: 29727616
Cell. 2014 Feb 27;156(5):1017-31
pubmed: 24581499
Dev Cell. 2016 Dec 19;39(6):638-652
pubmed: 27997823
J Cell Biol. 2002 Dec 9;159(5):807-19
pubmed: 12473689
Cell Biosci. 2015 Nov 04;5:60
pubmed: 26539288
Proteomics. 2009 Jun;9(12):3409-3412
pubmed: 29658196
EMBO J. 2001 Nov 15;20(22):6371-82
pubmed: 11707408
Mol Biol Cell. 2002 May;13(5):1501-11
pubmed: 12006648
Cold Spring Harb Perspect Biol. 2010 May;2(5):a000661
pubmed: 20452955
Curr Protein Pept Sci. 2012 Aug;13(5):467-81
pubmed: 22812528
Biology (Basel). 2017 Jan 24;6(1):
pubmed: 28125021
J Cell Sci. 2001 Mar;114(Pt 5):953-63
pubmed: 11181178
EMBO J. 2002 May 15;21(10):2496-506
pubmed: 12006501
Oncotarget. 2016 Apr 5;7(14):18159-70
pubmed: 26921248
Semin Cell Dev Biol. 2013 Apr;24(4):370-9
pubmed: 23416057
Oncogene. 2005 Aug 18;24(35):5401-13
pubmed: 15940266
J Biol Chem. 2012 Feb 10;287(7):4875-82
pubmed: 22167194
Oncogene. 1999 Dec 13;18(53):7644-55
pubmed: 10618704
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6549-54
pubmed: 22493223
J Cell Biol. 2012 Jul 9;198(1):11-21
pubmed: 22778276
Cancer. 2000 Apr 1;88(7):1623-32
pubmed: 10738221
Nat Cell Biol. 2000 Oct;2(10):730-6
pubmed: 11025664
J Biol Chem. 2003 Aug 1;278(31):29288-97
pubmed: 12759344
Cell Cycle. 2015;14(12):1763-4
pubmed: 26017778
FEBS Lett. 1997 Dec 22;420(1):25-7
pubmed: 9450543
Trends Genet. 2008 Sep;24(9):457-66
pubmed: 18675487
J Biol Chem. 1999 May 7;274(19):13111-7
pubmed: 10224064
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W325-30
pubmed: 24880689
Genes Dev. 2008 Nov 1;22(21):2926-31
pubmed: 18981471
Br J Cancer. 2004 Jul 19;91(2):355-8
pubmed: 15188009
Trends Cell Biol. 2001 May;11(5):184-7
pubmed: 11316590
Front Oncol. 2013 May 22;3:125
pubmed: 23734343
J Cell Biol. 2012 Dec 10;199(6):931-49
pubmed: 23209306
Curr Biol. 2014 Nov 17;24(22):2687-92
pubmed: 25447996
Mol Carcinog. 1997 Aug;19(4):243-53
pubmed: 9290701
Nat Rev Mol Cell Biol. 2009 Jul;10(7):478-87
pubmed: 19546858
Hum Mutat. 2014 Jun;35(6):756-65
pubmed: 24700732
Mol Biol Cell. 1999 Aug;10(8):2607-18
pubmed: 10436016
J Biol Chem. 2003 Aug 29;278(35):33134-41
pubmed: 12810724
J Cell Biol. 2010 Jul 12;190(1):25-34
pubmed: 20624899
Mol Cell. 2013 Jan 10;49(1):109-20
pubmed: 23177738
J Cell Biol. 1998 Oct 19;143(2):283-95
pubmed: 9786942
Cell Rep. 2016 Jun 21;15(12):2679-91
pubmed: 27292643
J Cell Sci. 2016 Dec 15;129(24):4439-4447
pubmed: 27856507
Cell. 1991 Aug 9;66(3):507-17
pubmed: 1651171
Genes Chromosomes Cancer. 2005 Sep;44(1):29-36
pubmed: 15898111
Cancer Res. 2007 Jan 1;67(1):160-6
pubmed: 17210695
Breast Cancer Res Treat. 2013 Jul;140(2):323-30
pubmed: 23860928
Proteomics. 2015 Feb;15(4):763-72
pubmed: 25367092
Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):E2205-14
pubmed: 22778409
Elife. 2018 Mar 08;7:
pubmed: 29517484
Cell. 1991 Aug 23;66(4):663-74
pubmed: 1652368
Clin Cancer Res. 2006 Jan 15;12(2):405-10
pubmed: 16428479
J Cell Biol. 2014 Mar 3;204(5):647-57
pubmed: 24567362
J Cell Biol. 1995 Mar;128(6):1185-96
pubmed: 7896881
Oncogene. 2005 Apr 21;24(18):2929-43
pubmed: 15735718
Nature. 1997 May 15;387(6630):296-9
pubmed: 9153395
Genes Dev. 2014 Jan 15;28(2):140-52
pubmed: 24402315