{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:54:56Z","timestamp":1791298496788,"version":"4.1.0"},"reference-count":42,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,11,1]]},"abstract":"<jats:p>ML-IAP [melanoma IAP (inhibitor of apoptosis)] is an anti-apoptotic protein that is expressed highly in melanomas where it contributes to resistance to apoptotic stimuli. The anti-apoptotic activity and elevated expression of IAP family proteins in many human cancers makes IAP proteins attractive targets for inhibition by cancer therapeutics. Small-molecule IAP antagonists that bind with high affinities to select BIR (baculovirus IAP repeat) domains have been shown to stimulate auto-ubiquitination and rapid proteasomal degradation of c-IAP1 (cellular IAP1) and c-IAP2 (cellular IAP2). In the present paper, we report ML-IAP proteasomal degradation in response to bivalent, but not monovalent, IAP antagonists. This degradation required ML-IAP ubiquitin ligase activity and was independent of c-IAP1 or c-IAP2. Although ML-IAP is best characterized in melanoma cells, we show that ML-IAP expression in normal mammalian tissues is restricted largely to the eye, being most abundant in ciliary body epithelium and retinal pigment epithelium. Surprisingly, given this pattern of expression, gene-targeted mice lacking ML-IAP exhibited normal intraocular pressure as well as normal retinal structure and function. The results of the present study indicate that ML-IAP is dispensable for both normal mouse development and ocular homoeostasis.<\/jats:p>","DOI":"10.1042\/bj20121103","type":"journal-article","created":{"date-parts":[[2012,8,3]],"date-time":"2012-08-03T08:22:32Z","timestamp":1343982152000},"page":"427-436","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Characterization of ML-IAP protein stability and physiological role <i>in vivo<\/i>"],"prefix":"10.1042","volume":"447","author":[{"given":"Eugene","family":"Varfolomeev","sequence":"first","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham","family":"Moradi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin\u00a0N.","family":"Dynek","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiping","family":"Zha","sequence":"additional","affiliation":[{"name":"Department of Pathology, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna\u00a0V.","family":"Fedorova","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Deshayes","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne\u00a0J.","family":"Fairbrother","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Newton","sequence":"additional","affiliation":[{"name":"Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Le Couter","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domagoj","family":"Vucic","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2012,10,5]]},"reference":[{"key":"2021112215261923100_B1","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1126\/science.7878463","article-title":"Mechanisms and genes of cellular suicide","volume":"267","author":"Steller","year":"1995","journal-title":"Science"},{"key":"2021112215261923100_B2","doi-asserted-by":"crossref","first-page":"2774","DOI":"10.1038\/sj.onc.1207522","article-title":"Caspase activation: stepping on the gas or releasing the brakes? Lessons from humans and flies","volume":"23","author":"Salvesen","year":"2004","journal-title":"Oncogene"},{"key":"2021112215261923100_B3","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/nrm830","article-title":"IAP proteins: blocking the road to death's door","volume":"3","author":"Salvesen","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021112215261923100_B4","doi-asserted-by":"crossref","first-page":"3124","DOI":"10.1158\/0008-5472.CAN-07-6622","article-title":"Microphthalmia-associated transcription factor is a critical transcriptional regulator of melanoma inhibitor of apoptosis in melanomas","volume":"68","author":"Dynek","year":"2008","journal-title":"Cancer Res."},{"key":"2021112215261923100_B5","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/S0960-9822(00)00781-8","article-title":"ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas","volume":"10","author":"Vucic","year":"2000","journal-title":"Curr. Biol."},{"key":"2021112215261923100_B6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nrd3627","article-title":"Targeting IAP proteins for therapeutic intervention in cancer","volume":"11","author":"Fulda","year":"2012","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2021112215261923100_B7","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1074\/jbc.M003670200","article-title":"Livin, a novel inhibitor of apoptosis protein family member","volume":"276","author":"Kasof","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112215261923100_B8","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1006\/bbrc.2000.4027","article-title":"KIAP, a novel member of the inhibitor of apoptosis protein family","volume":"279","author":"Lin","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112215261923100_B9","doi-asserted-by":"crossref","first-page":"8330","DOI":"10.1038\/sj.onc.1206973","article-title":"Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin\/ML-IAP\/KIAP gene","volume":"22","author":"Crnkovic-Mertens","year":"2003","journal-title":"Oncogene"},{"key":"2021112215261923100_B10","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/sj.embor.7400795","article-title":"Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family","volume":"7","author":"Eckelman","year":"2006","journal-title":"EMBO Rep."},{"key":"2021112215261923100_B11","doi-asserted-by":"crossref","first-page":"633","DOI":"10.2217\/fon.11.40","article-title":"Inhibitor of apoptosis proteins: fascinating biology leads to attractive tumor therapeutic targets","volume":"7","author":"Varfolomeev","year":"2011","journal-title":"Future Oncol."},{"key":"2021112215261923100_B12","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/cdd.2009.114","article-title":"Regulation of TNFRSF and innate immune signalling complexes by TRAFs and cIAPs","volume":"17","author":"Silke","year":"2010","journal-title":"Cell Death Differ."},{"key":"2021112215261923100_B13","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0092-8674(00)00008-8","article-title":"Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition","volume":"102","author":"Du","year":"2000","journal-title":"Cell"},{"key":"2021112215261923100_B14","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0092-8674(00)00009-X","article-title":"Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins","volume":"102","author":"Verhagen","year":"2000","journal-title":"Cell"},{"key":"2021112215261923100_B15","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1042\/BJ20041108","article-title":"Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP","volume":"385","author":"Vucic","year":"2005","journal-title":"Biochem. J."},{"key":"2021112215261923100_B16","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1042\/BJ20041800","article-title":"IAP proteins: sticking it to Smac","volume":"385","author":"Duckett","year":"2005","journal-title":"Biochem. J."},{"key":"2021112215261923100_B17","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nrm3143","article-title":"Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death","volume":"12","author":"Vucic","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021112215261923100_B18","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/nrm1621","article-title":"IAPs, RINGs and ubiquitylation","volume":"6","author":"Vaux","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021112215261923100_B19","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.cell.2007.10.030","article-title":"IAP antagonists induce autoubiquitination of c-IAPs, NF-\u03baB activation, and TNF\u03b1-dependent apoptosis","volume":"131","author":"Varfolomeev","year":"2007","journal-title":"Cell"},{"key":"2021112215261923100_B20","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.cell.2007.10.037","article-title":"IAP antagonists target cIAP1 to induce TNF\u03b1-dependent apoptosis","volume":"131","author":"Vince","year":"2007","journal-title":"Cell"},{"key":"2021112215261923100_B21","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.molcel.2008.05.014","article-title":"cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination","volume":"30","author":"Bertrand","year":"2008","journal-title":"Mol. Cell"},{"key":"2021112215261923100_B22","doi-asserted-by":"crossref","first-page":"17015","DOI":"10.1074\/jbc.M111.222919","article-title":"Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization","volume":"286","author":"Feltham","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021112215261923100_B23","doi-asserted-by":"crossref","first-page":"31633","DOI":"10.1074\/jbc.M804753200","article-title":"Structures of the cIAP2 RING domain reveal conformational changes associated with ubiquitin-conjugating enzyme (E2) recruitment","volume":"283","author":"Mace","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021112215261923100_B24","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1126\/science.1207862","article-title":"Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination","volume":"334","author":"Dueber","year":"2011","journal-title":"Science"},{"key":"2021112215261923100_B25","doi-asserted-by":"crossref","first-page":"24295","DOI":"10.1074\/jbc.C800128200","article-title":"c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor \u03b1 (TNF\u03b1)-induced NF-\u03baB activation","volume":"283","author":"Varfolomeev","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021112215261923100_B26","doi-asserted-by":"crossref","first-page":"29022","DOI":"10.1074\/jbc.M605116200","article-title":"The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-\u03baB activation independently of TRAF1 AND TRAF2","volume":"281","author":"Varfolomeev","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021112215261923100_B27","doi-asserted-by":"crossref","first-page":"4101","DOI":"10.1021\/jm300060k","article-title":"Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152)","volume":"55","author":"Flygare","year":"2012","journal-title":"J. Med. Chem."},{"key":"2021112215261923100_B28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1042\/BJ20081885","article-title":"Ubiquitin binding modulates IAP antagonist-stimulated proteasomal degradation of c-IAP1 and c-IAP2","volume":"417","author":"Blankenship","year":"2009","journal-title":"Biochem. J."},{"key":"2021112215261923100_B28a","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.2741\/3409","article-title":"Vision tests in the mouse: functional phenotyping with electroretinography","volume":"14","author":"Tanimoto","year":"2009","journal-title":"Front. Biosci."},{"key":"2021112215261923100_B29","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ccr.2007.07.004","article-title":"Frequent engagement of the classical and alternative NF-\u03baB pathways by diverse genetic abnormalities in multiple myeloma","volume":"12","author":"Annunziata","year":"2007","journal-title":"Cancer Cell"},{"key":"2021112215261923100_B30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ccr.2007.07.003","article-title":"Promiscuous mutations activate the noncanonical NF-\u03baB pathway in multiple myeloma","volume":"12","author":"Keats","year":"2007","journal-title":"Cancer Cell"},{"key":"2021112215261923100_B31","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.1038\/emboj.2010.300","article-title":"c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1\u00a0in TNF signalling","volume":"29","author":"Dynek","year":"2010","journal-title":"EMBO J."},{"key":"2021112215261923100_B32","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/sj.bjc.6604028","article-title":"Expression of inhibitor of apoptosis protein Livin in renal cell carcinoma and non-tumorous adult kidney","volume":"97","author":"Wagener","year":"2007","journal-title":"Br. J. Cancer"},{"key":"2021112215261923100_B33","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1001\/archopht.1995.01100030081025","article-title":"Optical coherence tomography of the human retina","volume":"113","author":"Hee","year":"1995","journal-title":"Arch. Ophthalmol."},{"key":"2021112215261923100_B34","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1126\/science.1957169","article-title":"Optical coherence tomography","volume":"254","author":"Huang","year":"1991","journal-title":"Science"},{"key":"2021112215261923100_B35","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0161-6420(95)31032-9","article-title":"Imaging of macular diseases with optical coherence tomography","volume":"102","author":"Puliafito","year":"1995","journal-title":"Ophthalmology"},{"key":"2021112215261923100_B36","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1158\/1078-0432.CCR-07-0729","article-title":"The inhibitor of apoptosis proteins as therapeutic targets in cancer","volume":"13","author":"Vucic","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"2021112215261923100_B37","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1128\/MCB.26.2.699-708.2006","article-title":"Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival","volume":"26","author":"Conte","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"2021112215261923100_B38","doi-asserted-by":"crossref","first-page":"16182","DOI":"10.1073\/pnas.0502828102","article-title":"Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance","volume":"102","author":"Silke","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215261923100_B39","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1152\/physrev.00021.2004","article-title":"The retinal pigment epithelium in visual function","volume":"85","author":"Strauss","year":"2005","journal-title":"Physiol. Rev."},{"key":"2021112215261923100_B40","first-page":"123","article-title":"Development of the ciliary body: a brief review","volume":"105","author":"Beebe","year":"1986","journal-title":"Trans. Ophthalmol. Soc. U.K."},{"key":"2021112215261923100_B41","doi-asserted-by":"crossref","first-page":"52","DOI":"10.2174\/1874364101004010052","article-title":"Aqueous humor dynamics: a review","volume":"4","author":"Goel","year":"2010","journal-title":"Open Ophthalmol. J."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/447\/3\/427\/670730\/bj4470427.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/447\/3\/427\/670730\/bj4470427.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T20:57:34Z","timestamp":1637614654000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/447\/3\/427\/45901\/Characterization-of-ML-IAP-protein-stability-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10,5]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,11,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20121103","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,10,5]]}}}