title: c-Cbl-mediated degradation of TRAIL receptors is responsible for the development of the early phase of TRAIL resistance.
abstract: We previously reported two modes of development of acquired TRAIL resistance: early phase and late phase [1]. In these studies, we observed that greater Akt activity and the expression of Bcl-xL were related mainly to the late phase of acquired TRAIL resistance. Recently we became aware of a possible mechanism of early phase TRAIL resistance development through internalization and degradation of TRAIL receptors (DR4 and DR5). Our current studies demonstrate that TRAIL receptors rapidly diminish at the membrane as well as the cytoplasm within 4h after TRAIL exposure, but recover completely after one or two days. Our studies also reveal that Cbl, a ubiquitously expressed cytoplasmic adaptor protein, is responsible for the rapid degradation of TRAIL receptors; Cbl binds to them and induces monoubiquitination of these receptors concurrent with their degeneration soon after TRAIL exposure, creating the early phase of acquired TRAIL resistance.
authors.affiliation: Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Song
authors.forename: Miroslaw Jerzy
authors.initials: MJ
authors.lastname: Szczepanski
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
authors.forename: Jee Young
authors.initials: JY
authors.lastname: An
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
authors.forename: Marco A
authors.initials: MA
authors.lastname: Alcala
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D006801:Humans; D016297:Mutagenesis, Site-Directed; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D054875:Ubiquitination
chemical_list: D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human