Notch Oncoproteins depend on γ-secretase/presenilin activity for processing and function
Notch Oncoproteins depend on γ-secretase/presenilin activity for processing and function
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DOI：
10.1074/jbc.m309252200
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发表时间：
2004-07-16
影响因子：
4.8
通讯作者：
Kitajewski, J
中科院分区：
文献类型：
--
作者：
Das, I;Craig, C;Kitajewski, J
在正常发育期间，Notch受体信号传导在调节许多细胞命运决定中是重要的。截短Notch受体的细胞外结构域的突变可引起异常信号传导并促进不受调节的细胞生长。我们已经研究了两种类型的截短的Notch癌蛋白，它们是由前病毒插入Notch 4基因（Notch 4/int-3）或涉及Notch 1基因的染色体易位（TAN-1）引起的。Notch 4/int-3和TAN-1癌蛋白都缺乏大部分或全部的胞外域。正常的Notch信号需要γ-分泌酶/早老素介导的蛋白水解加工，但Notch癌蛋白是否也依赖于γ-分泌酶/早老素活性尚不清楚。我们证明，Notch 4/int-3诱导的下游转录因子CSL的激活在缺乏早老素的细胞中被废除，或者用γ-分泌酶/早老素的药理学抑制剂处理。此外，我们发现，Notch 4/int-3和TAN-1积累在细胞表面，早老蛋白依赖性裂解发生时，γ-分泌酶/早老蛋白活性被抑制。γ-分泌酶/早老素抑制有效地阻断了对Notch 4/int-3的细胞应答，但不能阻断对TAN-1的细胞应答，这显然是因为一些TAN-1多肽缺乏跨膜结构域，并且不需要γ-分泌酶/早老素活性来进入核。这些研究强调了γ-分泌酶/早老素抑制剂在Notch相关肿瘤靶向治疗中的潜在用途和局限性。
During normal development Notch receptor signaling is important in regulating numerous cell fate decisions. Mutations that truncate the extracellular domain of Notch receptors can cause aberrant signaling and promote unregulated cell growth. We have examined two types of truncated Notch oncoproteins that arise from proviral insertion into the Notch4 gene (Notch4/int-3) or a chromosomal translocation involving the Notch1 gene (TAN-1). Both Notch4/int-3 and TAN-1 oncoproteins lack most or all of their ectodomain. Normal Notch signaling requires gamma-secretase/presenilin-mediated proteolytic processing, but whether Notch oncoproteins are also dependent on gamma-secretase/presenilin activity is not known. We demonstrate that Notch4/int-3-induced activation of the downstream transcription factor, CSL, is abrogated in cells deficient in presenilins or treated with a pharmacological inhibitor of gamma-secretase/presenilins. Furthermore, we find that both Notch4/int-3 and TAN-1 accumulate at the cell surface, where presenilin-dependent cleavage occurs, when gamma-secretase/presenilin activity is inhibited. gamma-Secretase/presenilin inhibition effectively blocks cellular responses to Notch4/int-3, but not TAN-1, apparently because some TAN-1 polypeptides lack transmembrane domains and do not require gamma-secretase/presenilin activity for nuclear access. These studies highlight potential uses and limitations of gamma-secretase/presenilin inhibitors in targeted therapy of Notch-related neoplasms.