title: Characterization of ML-IAP protein stability and physiological role in vivo.
abstract: 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.
authors.affiliation: Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Varfolomeev
authors.forename: Elham
authors.initials: E
authors.lastname: Moradi
authors.forename: Jasmin N
authors.initials: JN
authors.lastname: Dynek
authors.forename: Jiping
authors.initials: J
authors.lastname: Zha
authors.forename: Anna V
authors.initials: AV
authors.lastname: Fedorova
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.forename: Jennifer
authors.initials: J
authors.lastname: Le Couter
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D005123:Eye / Q000098:blood supply / Q000378:metabolism*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007429:Intraocular Pressure; D008297:Male; D008545:Melanoma; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D012160:Retina / Q000033:anatomy & histology / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex