Down-regulation of the transcriptional mediator subunit Med1 contributes to the loss of expression of metastasis-associated dapk1 in human cancers and cancer cells.
Down-regulation of the transcriptional mediator subunit Med1 contributes to the loss of expression of metastasis-associated dapk1 in human cancers and cancer cells.
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DOI：
10.1002/ijc.24493
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发表时间：
2009-10-01
影响因子：
6.4
通讯作者：
Kalvakolanu DV
中科院分区：
文献类型：
--
作者：
Gade P;Singh AK;Roy SK;Reddy SP;Kalvakolanu DV
DAPK1是一种受Ca+2/钙调蛋白调节的丝氨酸/苏氨酸激酶，是一种主要的肿瘤抑制因子，在多种肿瘤类型中均有表达。然而，导致这一现象的机制尚不清楚。我们最近发现，CCAAT/增强子结合蛋白-β(C/EBP-β)是基础和干扰素γ(干扰素-γ)诱导许多细胞类型的DAPK1表达所必需的。C/eBP-β与转录介体相互作用，转录介体是一个多亚单位复合体，以干扰素-γ依赖的方式将增强子结合的转录因子与基础转录机制偶联，以调节DAPK1的表达。具体地说，MED1(TRAP220/PBP/DRIP220/CRSP220)亚单位与DAPK1Cre/ATF位点上的增强子结合C/EBP-β以干扰素-γ依赖的方式刺激基因表达。因此，我们研究了在人类癌症中导致DAPK1表达缺失的机制是否与未能将C/eBP-β和/或MED1招募到DAPK1启动子有关。我们比较了正常细胞系和癌细胞系中Cre/ATF位点dapk1启动子上这些因子的相对占有率。在人类癌细胞系中，这些因子与dapk1启动子的Cre/ATF位点的结合显著低于正常细胞。我们发现，在一些原发人类肺癌中，MED1的表达缺失与相应的DAPK1的表达缺失相关。癌细胞系的MED1水平显著低于正常对照组。重要的是，我们发现MED1的修复诱导了这些癌细胞中DAPK1的表达，并减弱了它们在体内的转移潜能。我们的研究揭示了在癌细胞系中限制dapk1表达的关键参数。
DAPK1, a ca+2/calmodulin regulated serine/threonine kinase, is a major tumor suppressor, whose expression is lost in multiple tumor types. However, the mechanisms contributing to it are unclear. We have recently shown that CCAAT/Enhancer binding protein-β (C/EBP-β) is required for the basal and interferon γ (IFN-γ)-induced expression of dapk1 in many cell types. C/EBP-β interacts with the transcriptional Mediator, a multi-subunit complex that couples enhancer bound transcription factors to the basal transcriptional machinery in an IFN-γ dependent manner for regulating dapk1 expression. Specifically, the Med1 (TRAP220/PBP/DRIP220/CRSP220) subunit associates with the enhancer bound C/EBP-β at the CRE/ATF site of dapk1 in an IFN-γ dependent manner for stimulating gene expression. Therefore, we investigated if the mechanism responsible for the loss of dapk1 expression in human cancers involves a failure to recruit C/EBP-β and/or Med1 to the dapk1 promoter. We compared the relative occupancy of these factors at the dapk1 promoter at CRE/ATF sites in normal and cancer cell lines. A significantly lower binding of these factors to the CRE/ATF site of dapk1 promoter occurred in human cancer cell lines than in normal cells. We show that loss of Med1 expression correlates with a corresponding loss of dapk1 expression in a number of primary human lung carcinomas. Med1 levels were significantly lower in cancer cell lines than in normal controls. Importantly, we show that restoration of Med1 induces the expression of dapk1 in these cancer cells and also attenuates their metastatic potential in vivo. Our studies reveal a critical parameter limiting dapk1 expression in cancer cell lines.
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影响因子：
11.2
作者：
Adiseshaiah, Pavan;Lindner, Daniel J.;Reddy, Sekhar P.
通讯作者：
Reddy, Sekhar P.
影响因子：
10.5
作者：
DEISS, LP;FEINSTEIN, E;KIMCHI, A
通讯作者：
KIMCHI, A
影响因子：
11.4
作者：
Kitabayashi, I;Aikawa, Y;Ohki, M
通讯作者：
Ohki, M
DOI：
10.1073/pnas.93.1.465
发表时间：
1996-01-09
影响因子：
11.1
作者：
Chen, PL;Riley, DJ;Lee, WH
通讯作者：
Lee, WH
影响因子：
64.8
作者：
Ge, K;Guermah, M;Roeder, RG
通讯作者：
Roeder, RG