Tissue transglutaminase constitutively activates HIF-1α promoter and nuclear factor-κB via a non-canonical pathway.
Tissue transglutaminase constitutively activates HIF-1α promoter and nuclear factor-κB via a non-canonical pathway.
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组织转谷氨酰胺酶组成性地通过非经典途径激活HIF-1α启动子和核因子-κB。
DOI：
10.1371/journal.pone.0049321
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mehta K
中科院分区：
文献类型：
--
作者：
Kumar S;Mehta K
核因子κ B（NF-κB）的组成性激活与肿瘤发生和进展有关，包括转移、化疗耐药性和放射耐药性。然而，导致NF-κB组成性激活的分子机制知之甚少。在此，我们发现促炎蛋白组织转氨酶（TG 2）的慢性表达通过NF-κB的组成性激活重新编程上皮细胞中的转录调控网络。TG 2诱导的NF-κB与低氧诱导因子1 α（HIF-1α）启动子中的NF-κB结合位点结合，导致其在转录和蛋白水平的表达增加，即使在常氧条件下也是如此。TG 2/NF-κ B诱导的HIF-1被认为是一些转录抑制因子如Zeb 1、Zeb 2、Snail和Twist表达增加的关键。与肿瘤坏死因子-α（TNFα）不同，TG 2不需要IκB激酶（IKK）来激活NF-κB。我们的数据表明，TG 2与IκBα结合，并通过非蛋白酶体途径导致其快速降解。重要的是，TG 2的无催化活性（C277 S）突变形式在激活NF-κB和诱导HIF-1表达方面与野生型TG 2一样有效。我们还发现，TG 2相互作用与p65/RelA蛋白，无论是在胞浆和核隔室。TG 2/p65（NF-κB）复合物与HIF-1启动子结合并诱导其转录调节。抑制TG 2或p65/RelA也抑制HIF-1α的表达并减弱Zeb 1、Zeb 2和Twist的表达。据我们所知，这些发现首次显示了TG 2、NF-κB和HIF-1α之间的直接联系，证明了TG 2在癌症进展中的重要作用。
Constitutive activation of nuclear factor kappa B (NF-κB) has been linked with carcinogenesis and cancer progression, including metastasis, chemoresistance, and radiation resistance. However, the molecular mechanisms that result in constitutive activation of NF-κB are poorly understood. Here we show that chronic expression of the pro-inflammatory protein tissue transglutaminase (TG2) reprograms the transcription regulatory network in epithelial cells via constitutive activation of NF-κB. TG2-induced NF-κB binds the functional NF-κB binding site in hypoxia-inducible factor-1 (HIF-1α) promoter and results in its increased expression at transcription and protein levels even under normoxic conditions. TG2/NF-κB-induced HIF-1 was deemed essential for increased expression of some transcription repressors, like Zeb1, Zeb2, Snail, and Twist. Unlike tumor necrosis factor-alpha (TNFα), TG2 did not require IκB kinase (IKK) for NF-κB activation. Our data suggest that TG2 binds with IκBα and results in its rapid degradation via a non-proteasomal pathway. Importantly, the catalytically inactive (C277S) mutant form of TG2 was as effective as was wild-type TG2 in activating NF-κB and inducing HIF-1 expression. We also found that TG2 interacted with p65/RelA protein, both in the cytosolic and the nuclear compartment. The TG2/p65(NF-κB) complex binds to the HIF-1 promoter and induced its transcriptional regulation. Inhibition of TG2 or p65/RelA also inhibited the HIF-1α expression and attenuated Zeb1, Zeb2, and Twist expression. To our knowledge, these findings show for the first time a direct link between TG2, NF-κB, and HIF-1α, demonstrating TG2's important role in cancer progression.
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影响因子：
29
作者：
Baker RG;Hayden MS;Ghosh S
通讯作者：
Ghosh S
影响因子：
11.2
作者：
Hwang JY;Mangala LS;Fok JY;Lin YG;Merritt WM;Spannuth WA;Nick AM;Fiterman DJ;Vivas-Mejia PE;Deavers MT;Coleman RL;Lopez-Berestein G;Mehta K;Sood AK
通讯作者：
Sood AK
DOI：
10.1186/bcr3085
发表时间：
2012-01-06
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kumar A;Xu J;Sung B;Kumar S;Yu D;Aggarwal BB;Mehta K
通讯作者：
Mehta K
影响因子：
4.8
作者：
Lee, JM;Kim, YS;Kim, SY
通讯作者：
Kim, SY
影响因子：
4.7
作者：
Cao, Liyun;Petrusca, Daniela N.;Matei, Daniela
通讯作者：
Matei, Daniela