c-Cbl-mediated degradation of TRAIL receptors is responsible for the development of the early phase of TRAIL resistance |
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Authors: | Jae J Song Miroslaw Jerzy Szczepanski So Young Kim Joo-Hang Kim Jee Young An Yong Tae Kwon Marco A Alcala David L Bartlett Yong J Lee |
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Institution: | 1. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuchang, 430060 Wuhan, PR China;2. Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, PR China |
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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 4 h 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. |
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