Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Cell Signal. 2010 Mar;22(3):553-63. doi: 10.1016/j.cellsig.2009.11.012.
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.
我们之前报道了获得性 TRAIL 抵抗的两种发展模式：早期阶段和晚期阶段[1]。在这些研究中，我们观察到 Akt 活性的增加和 Bcl-xL 的表达主要与获得性 TRAIL 抵抗的晚期阶段有关。最近，我们意识到 TRAIL 受体的内化和降解可能是早期 TRAIL 抵抗发展的一种机制。我们目前的研究表明，TRAIL 受体在 TRAIL 暴露后 4 小时内迅速从细胞膜和细胞质中消失，但在 1 或 2 天后完全恢复。我们的研究还揭示了 Cbl，一种广泛表达的细胞质衔接蛋白，负责 TRAIL 受体的快速降解；Cbl 与它们结合，并在 TRAIL 暴露后不久诱导这些受体的单泛素化及其退化，从而产生获得性 TRAIL 抵抗的早期阶段。
