Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.
Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.
复制标题
DOI：
10.1016/j.ccr.2009.05.009
复制
发表时间：
2009-07-07
期刊：
影响因子：
50.3
通讯作者：
Cichowski K
中科院分区：
文献类型：
--
作者：
McGillicuddy LT;Fromm JA;Hollstein PE;Kubek S;Beroukhim R;De Raedt T;Johnson BW;Williams SM;Nghiemphu P;Liau LM;Cloughesy TF;Mischel PS;Parret A;Seiler J;Moldenhauer G;Scheffzek K;Stemmer-Rachamimov AO;Sawyers CL;Brennan C;Messiaen L;Mellinghoff IK;Cichowski K
NF1 肿瘤抑制因子的功能缺失突变导致 Ras 信号传导失调，并驱动 I 型家族性癌症综合征神经纤维瘤病的肿瘤发生。然而，NF1 失活在多大程度上促进散发性肿瘤发生尚不清楚。在这里，我们报告说，NF1 在散发性神经胶质瘤中通过两种机制失活：过度蛋白酶体降解和遗传丢失。 NF1 蛋白不稳定是由蛋白激酶 C (PKC) 过度激活引发的，并赋予对 PKC 抑制剂的敏感性。然而，仅当 p53 失活时才会发生完全的遗传丢失，从而介导对 mTOR 抑制剂的敏感性。这些研究揭示了 NF1 失活在散发性胶质瘤发生中的不断扩大的作用，并说明了如何在遗传上不同的肿瘤中利用不同的失活机制，从而影响治疗敏感性。肿瘤抑制因子在人类癌症中经常发生突变；然而，抑癌蛋白的过度蛋白酶体破坏也会促进肿瘤发生。在这里，我们发现由于 PKC 过度激活，NF1 蛋白在散发性 GBM 中不稳定。值得注意的是，这种不稳定导致对 PKC 抑制剂的敏感性。相比之下，具有 NF1 突变的 GBM 的一个单独子集对 PKC 抑制剂不敏感，但对 mTOR 抑制剂敏感。这些发现揭示了 NF1 失活在神经胶质瘤发生中的广泛作用，并说明了如何在同一肿瘤类型中利用不同的失活机制。此外，他们强调了阐明肿瘤发生的分子机制的重要性，因为这些知识对于开发个性化疗法可能至关重要。
Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1-inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1-inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity. Tumor suppressors are often mutated in human cancer; however, the excessive proteasomal destruction of tumor suppressor proteins also promotes tumorigenesis. Here we show that the NF1 protein is destabilized in sporadic GBMs as a consequence of the hyperactivation of PKC. Notably, this destabilization confers sensitivity to PKC inhibitors. In contrast, a separate subset of GBMs that possess NF1 mutations are insensitive to PKC inhibitors but are sensitive to mTOR inhibitors. These findings reveal a broad role for NF1-inactivation in gliomagenesis and illustrate how different mechanisms of inactivation are utilized in the same tumor-type. Moreover they highlight the importance of elucidating the molecular mechanisms that underlie tumorigenesis, as such knowledge may be essential for developing personalized therapies.
登录
查看更多内容
影响因子：
64.5
作者：
LI, Y;BOLLAG, G;CAWTHON, R
通讯作者：
CAWTHON, R
雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
56.9
作者：
Marais, R;Light, Y;Marshall, CJ
通讯作者：
Marshall, CJ
影响因子：
64.5
作者：
CAWTHON, RM;WEISS, R;WHITE, R
通讯作者：
WHITE, R