c-Cbl-mediated degradation of TRAIL receptors is responsible for the development of the early phase of TRAIL resistance.
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.
Song
Jae J
JJ
Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Szczepanski
Miroslaw Jerzy
MJ
Kim
So Young
SY
Kim
Joo-Hang
JH
An
Jee Young
JY
Kwon
Yong Tae
YT
Alcala
Marco A
MA
Bartlett
David L
DL
Lee
Yong J
YJ
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
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