title: ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells.
abstract: RAS mutations occur frequently in human cancer and activated RAS signalling contributes to tumour development and progression. Apart from its oncogenic effects on cell growth, active RAS has tumour-suppressive functions via its ability to induce cellular senescence and apoptosis. RAS is known to induce p53-dependent cell cycle arrest, yet its effect on p53-dependent apoptosis remains unclear. We report here that apoptosis-stimulating protein of p53 (ASPP) 1 and 2, two activators of p53, preferentially bind active RAS via their N-terminal RAS-association domains (RAD). Additionally, ASPP2 colocalises with and contributes to RAS cellular membrane localisation and potentiates RAS signalling. In cancer cells, ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53. Thus, loss of ASPP1 and ASPP2 in human cancer cells may contribute to the full transforming property of RAS oncogene.
authors: Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research Ltd, University of Oxford, Oxford, UK.
authors: Y
authors: Y
authors: Wang
authors: N
authors: N
authors: Godin-Heymann
authors: X
authors: X
authors: Dan Wang
authors: D
authors: D
authors: Bergamaschi
authors: S
authors: S
authors: Llanos
authors: X
authors: X
authors: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498406:PPP1R13B protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C090468:TP53BP2 protein, human; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins
references: Curr Biol. 2010 Aug 10;20(15):1408-14
references: 20619648
references: Mol Cell Biol. 1997 Jan;17(1):506-18
references: 8972231
references: J Mol Biol. 2007 Aug 24;371(4):948-58
references: 17594908
references: Oncogene. 1999 Sep 2;18(35):4974-82
references: 10490832
references: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4390-5
references: 19251665
references: Genes Dev. 2010 Nov 1;24(21):2430-9
references: 21041411
references: Nature. 1998 Sep 10;395(6698):125-6
references: 9744268
references: Cell. 1997 Nov 28;91(5):649-59
references: 9393858
references: Dev Cell. 2010 Jul 20;19(1):126-37
references: 20619750
references: Genes Dev. 2010 Nov 1;24(21):2420-9
references: 21041410
references: Cell Death Differ. 2011 Feb;18(2):304-14
references: 20798689
references: Genes Dev. 1998 Aug 1;12(15):2424-33
references: 9694806
references: Cell Death Differ. 2005 Apr;12(4):369-76
references: 15731768
references: Mol Cell. 2001 Oct;8(4):781-94
references: 11684014
references: Cell. 1996 Oct 18;87(2):159-70
references: 8861899
references: Genes Dev. 1997 Jul 15;11(14):1840-52
references: 9242491
references: Mol Cell Biol. 2004 Feb;24(3):1341-50
references: 14729977
references: Genes Dev. 2006 May 15;20(10):1262-7
references: 16702401
references: Nat Rev Cancer. 2003 Jan;3(1):11-22
references: 12509763
references: EMBO J. 1998 Sep 1;17(17):5001-14
references: 9724636
references: Cell. 1997 Mar 7;88(5):593-602
references: 9054499
references: Cell. 1998 Mar 20;92(6):713-23
references: 9529248
references: J Biol Chem. 1999 Jul 2;274(27):18857-63
references: 10383381
references: Genes Dev. 1998 Aug 1;12(15):2434-42
references: 9694807
references: Nat Genet. 2003 Feb;33(2):162-7
references: 12524540
references: Nature. 1997 Feb 6;385(6616):544-8
references: 9020362
references: Oncogene. 1996 Oct 17;13(8):1709-19
references: 8895517
references: Oncogene. 1996 Aug 15;13(4):739-48
references: 8761295
references: Nat Rev Clin Oncol. 2011 Apr 05;8(8):492-503
references: 21468131
references: Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13325-30
references: 22847423
references: Biochim Biophys Acta. 2008 Dec;1786(2):178-87
references: 18541156
references: Oncogene. 2002 Feb 28;21(10):1527-38
references: 11896581
references: Genes Dev. 2000 Aug 15;14(16):2015-27
references: 10950866
references: Nat Rev Clin Oncol. 2010 Sep;7(9):493-507
references: 20551942
references: Oncogene. 2010 Aug 19;29(33):4658-70
references: 20562906
references: Mol Cell Biol. 1996 Jul;16(7):3884-92
references: 8668206
references: Nat Genet. 2006 Oct;38(10):1133-41
references: 16964264
references: Nat Cell Biol. 1999 May;1(1):20-6
references: 10559859
references: Oncogene. 2003 Dec 8;22(56):8999-9006
references: 14663478
references: Dev Biol. 2008 Apr 1;316(1):149-59
references: 18304521