Differential IKK/NF-κB Activity Is Mediated by TSC2 through mTORC1 in PTEN-Null Prostate Cancer and Tuberous Sclerosis Complex Tumor Cells.
Differential IKK/NF-κB Activity Is Mediated by TSC2 through mTORC1 in PTEN-Null Prostate Cancer and Tuberous Sclerosis Complex Tumor Cells.
复制标题
DOI：
10.1158/1541-7786.mcr-15-0213
复制
发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Dan HC
中科院分区：
文献类型：
--
作者：
Gao Y;Gartenhaus RB;Lapidus RG;Hussain A;Zhang Y;Wang X;Dan HC
丝氨酸/苏氨酸蛋白激酶Akt通过磷酸化不同的下游底物，在调节细胞增殖、生长和存活中起关键作用。哺乳动物雷帕霉素靶点（mTOR）是Akt促进肿瘤发生的关键靶点。据报道，Akt通过磷酸化和抑制结节硬化复合体（TSC）蛋白TSC2激活mTOR。先前的研究表明，在PTEN缺乏的情况下，mTOR通过促进Akt下游的IKK活性来激活IKK/NF-κB信号。本研究探讨肿瘤抑制因子TSC2在pten缺失前列腺癌和TSC2突变肿瘤细胞中调控IKK/NF-κB活性的机制作用。结果表明，在PTEN缺失的环境中，TSC2抑制Akt下游和mTORC1上游的IKK/NF-κB活性。然而，在TSC2突变的肿瘤细胞中，TSC2促进Akt和mTORC1上游的IKK/NF-κB活性。这些数据表明，TSC2负或正调节IKK/NF-κB活性，这取决于遗传背景。
The serine/threonine protein kinase Akt plays a critical role in regulating proliferation, growth and survival through phosphorylation of different downstream substrates. The mammalian target of rapamycin (mTOR) is a key target for Akt to promote tumorigenesis. It has been reported that Akt activates mTOR through phosphorylation and inhibition of the tuberous sclerosis complex (TSC) protein TSC2. Previously it was demonstrated that mTOR activates IKK/NF-κB signaling by promoting IKK activity downstream of Akt in conditions deficient of PTEN. In the current study, the mechanistic role of the tumor suppressor TSC2 was investigated in the regulation of IKK/NF-κB activity in PTEN-null prostate cancer and in TSC2 mutated tumor cells. The results demonstrate that TSC2 inhibits IKK/NF-κB activity downstream of Akt and upstream of mTORC1 in a PTEN deficient environment. However, TSC2 promotes IKK/NF-κB activity upstream of Akt and mTORC1 in TSC2 mutated tumor cells. These data indicate that TSC2 negatively or positively regulates IKK/NF-κB activity in a context-dependent manner depending on the genetic background.