Tumor suppressor ras association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis.
Epigenetic silencing of RASSF (Ras association domain family) genes RASSF1 and RASSF5 (also called NORE1) by CpG hypermethylation is found frequently in many cancers. Although the physiological roles of RASSF1 have been studied in some detail, the exact functions of RASSF5 are not well understood. Here, we show that RASSF5 plays an important role in mediating apoptosis in response to death receptor ligands, TNF-α and TNF-related apoptosis-inducing ligand. Depletion of RASSF5 by siRNA significantly reduced TNF-α-mediated apoptosis, likely through its interaction with proapoptotic kinase MST1, a mammalian homolog of Hippo. Consistent with this, siRNA knockdown of MST1 also resulted in resistance to TNF-α-induced apoptosis. To further study the role of Rassf5 in vivo, we generated Rassf5-deficient mouse. Inactivation of Rassf5 in mouse embryonic fibroblasts (MEFs) resulted in resistance to TNF-α- and TNF-related apoptosis-inducing ligand-mediated apoptosis. Importantly, Rassf5-null mice were significantly more resistant to TNF-α-induced apoptosis and failed to activate Mst1. Loss of Rassf5 also resulted in spontaneous immortalization of MEFs at earlier passages than the control MEFs, and Rassf5-null immortalized MEFs, but not the immortalized wild type MEFs, were fully transformed by K-RasG12V. Together, our results demonstrate a direct role for RASSF5 in death receptor ligand-mediated apoptosis and provide further evidence for RASSF5 as a tumor suppressor.
Park
Jikyoung
J
Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kang
Soo Im
SI
Lee
Sun-Young
SY
Zhang
Xian F
XF
Kim
Myoung Shin
MS
Beers
Lisa F
LF
Lim
Dae-Sik
DS
Avruch
Joseph
J
Kim
Ho-Shik
HS
Lee
Sean Bong
SB
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C455831:Rassf5 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases
Sci Signal. 2009 Sep 29;2(90):ra59
19797269
J Cell Biol. 1963 May;17:299-313
13985244
Biochem J. 2004 Jul 15;381(Pt 2):453-62
15109305
Curr Biol. 2002 Feb 19;12(4):253-65
11864565
J Biol Chem. 2002 Dec 13;277(50):47991-8001
12384512
Mol Cell Biol. 2002 Jun;22(12):4309-18
12024041
J Immunol. 1994 Aug 15;153(4):1778-88
8046244
J Biol Chem. 1998 Mar 6;273(10):5439-42
9488663
Curr Biol. 2003 Dec 2;13(23):R899-900
14654011
Oncogene. 2003 Feb 13;22(6):947-54
12584574
Nat Cell Biol. 2004 Feb;6(2):129-37
14743218
Biochim Biophys Acta. 2007 Sep;1776(1):58-85
17692468
J Exp Med. 1987 Mar 1;165(3):657-63
3819645
Nat Rev Cancer. 2007 Mar;7(3):182-91
17318211
Cell. 2003 May 16;113(4):507-17
12757711
Gastroenterology. 2006 Apr;130(4):1117-28
16618406
Curr Biol. 2008 Dec 9;18(23):1889-95
19062280
Curr Biol. 2007 Apr 17;17(8):700-5
17379520
Mol Cell Biol. 2005 Sep;25(18):8356-67
16135822
EMBO J. 1998 Apr 15;17(8):2224-34
9545236
J Cell Sci. 2007 Sep 15;120(Pt 18):3163-72
17878233
Oncogene. 2003 Nov 6;22(50):8125-36
14603253
J Biol Chem. 2009 Apr 24;284(17):11001-5
19091744
Oncogene. 2002 Feb 21;21(9):1381-90
11857081
Cancer Res. 2005 Jan 1;65(1):92-8
15665283
Biochim Biophys Acta. 2009 Dec;1796(2):114-28
19344752
Mol Cell Biol. 2008 Jul;28(14):4520-35
18474619
Nat Immunol. 2006 Sep;7(9):919-28
16892067
J Biol Chem. 2007 Oct 19;282(42):30836-44
17726016
Oncogene. 2003 Oct 2;22(43):6794-801
14555992
Mol Cell. 2005 Jun 10;18(6):637-50
15949439
Proc Natl Acad Sci U S A. 2007 May 29;104(22):9236-41
17517604
Cancer Res. 1998 Nov 1;58(21):4888-94
9809995
Cell. 2006 Jun 2;125(5):987-1001
16751106
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10148-53
11517310
Mol Cell. 2007 Sep 21;27(6):962-75
17889669
Cancer Res. 2004 Jun 15;64(12):4244-50
15205337
Nat Genet. 2000 Jul;25(3):315-9
10888881
Curr Biol. 2006 Dec 19;16(24):2459-65
17174922
Cancer Res. 2006 Mar 1;66(5):2562-9
16510573
Oncogene. 2002 Apr 18;21(17):2713-20
11965544
Mol Cell Biol. 2007 Aug;27(15):5514-22
17548476
Nat Immunol. 2004 Oct;5(10):1045-51
15361866