Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase
Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase
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DOI：
10.1038/sj.onc.1208996
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发表时间：
2006-01
期刊：
影响因子：
8
通讯作者：
K. Nagano;C. Itagaki;T. Izumi;Kazuto Nunomura;Yasushi Soda;Kenzaburo Tani;Nobuhiro Takahashi;Tadaomi Takenawa;Toshiaki Isobe
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文献类型：
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作者：
K. Nagano;C. Itagaki;T. Izumi;Kazuto Nunomura;Yasushi Soda;Kenzaburo Tani;Nobuhiro Takahashi;Tadaomi Takenawa;Toshiaki Isobe
视网膜母细胞瘤(Rb)基因产物是一种肿瘤抑制基因，在许多类型的人类癌症中发生突变或失活。虽然Rb被认为是Abl蛋白酪氨酸激酶的上游负调控因子，但我们认为Rb也是Abl的下游效应因子，对Abl依赖的人类肿瘤细胞，包括bcr/abl阳性的慢性粒细胞白血病(CML)的生存起着积极的作用。我们发现，在Abl依赖的肿瘤细胞中，Rb在酪氨酸处被结构性磷酸化，而Abl在分子的C-末端结构域中特异性地在Y805处磷酸化Rb。我们还表明，Rb的异位表达通过抑制Abl酪氨酸激酶活性诱导Abl依赖的肿瘤细胞凋亡，并且Rb诱导的凋亡被Abl催化的Rb在Y805的磷酸化所折衷。此外，RNA干扰沉默内源性Rb可诱导Abl依赖的肿瘤细胞发生凋亡。因此，我们的发现表明，Abl催化的Rb酪氨酸磷酸化对于Abl依赖的人类肿瘤细胞的生存是必要的，并增加了这种磷酸化的Rb可能成为诱导Abl依赖的肿瘤细胞(如bcr/Abl阳性的CML)凋亡的癌症治疗的分子靶点的可能性。
The retinoblastoma (Rb) gene product is a tumor suppressor that is mutated or inactivated in many types of human cancers. Although Rb is known to be an upstream negative regulator of Abl protein tyrosine kinase, we propose here that Rb also functions as a downstream effector of Abl that plays a positive role in survival of Abl-dependent human tumor cells, including Bcr/Abl-positive chronic myelogenous leukemia (CML). We show that Rb is constitutively phosphorylated at tyrosine in Abl-dependent tumor cells, and that Abl phosphorylates Rb specifically at Y805 within the C-terminal domain of the molecule. We also show that ectopic expression of Rb induces apoptosis in Abl-dependent tumor cells by inhibiting the Abl tyrosine kinase activity, and that Rb-induced apoptosis is compromised by Abl-catalysed phosphorylation of Rb at Y805. Furthermore, the silencing of endogenous Rb by RNA interference induced apoptosis in Abl-dependent tumor cells. Thus, our findings suggest that Abl-catalysed tyrosine phosphorylation of Rb is necessary for survival of Abl-dependent human tumor cells, and raises the possibility that this phosphorylated Rb can be a molecular target for cancer therapy aimed at inducing apoptosis of Abl-dependent tumor cells, such as Bcr/Abl-positive CML.