title: Tumor suppressor ras association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis.
abstract: 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.
authors.affiliation: Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jikyoung
authors.initials: J
authors.lastname: Park
authors.forename: Soo Im
authors.initials: SI
authors.lastname: Kang
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Xian F
authors.initials: XF
authors.lastname: Zhang
authors.forename: Myoung Shin
authors.initials: MS
authors.lastname: Kim
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Beers
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
authors.forename: Ho-Shik
authors.initials: HS
authors.lastname: Kim
authors.forename: Sean Bong
authors.initials: SB
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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
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