Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer.
Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer.
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人DNAJ同源物亚家族的结构和功能A成员1（DNAJA1）及其与胰腺癌的关系。
DOI：
10.1021/bi401329a
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发表时间：
2014-03-04
期刊：
影响因子：
2.9
通讯作者：
Powers, Robert
中科院分区：
文献类型：
--
作者：
Stark, Jaime L.;Mehla, Kamiya;Chaika, Nina;Acton, Thomas B.;Xiao, Rong;Singh, Pankaj K.;Monteione, Gaetano T.;Powers, Robert
胰腺癌的5年生存率为5.5%，尽管付出了巨大的努力，但在过去的25年里没有得到改善。因此，迫切需要确定真正新颖但可药用的蛋白质靶点用于药物发现。人类蛋白质DnaJ同源物亚家族A成员1（DNAJA 1）先前显示在胰腺癌细胞中下调5倍，并且已被靶向作为胰腺癌的生物标志物，但对于DNAJA 1或人类基因组中编码的DnaJ家族的其他成员的特定生物学功能知之甚少。我们的研究结果表明，DNAJA 1的过表达抑制了致癌转录因子c-Jun的应激反应能力，并导致细胞存活减少。DNAJA 1可能通过形成抑制JNK通路、c-Jun过度磷酸化和胰腺癌细胞中发现的抗凋亡状态的复合物来激活DnaK蛋白。结合生物信息学分析和配体亲和筛选，DNAJA 1 J结构域的高质量核磁共振溶液结构鉴定了潜在的DnaK结合位点，该位点也被预测与抑制性结合位点重叠，表明DNAJA 1活性受到高度调节。
Pancreatic cancer has a dismal 5 year survival rate of 5.5% that has not been improved over the past 25 years despite an enormous amount of effort. Thus, there is an urgent need to identify truly novel yet druggable protein targets for drug discovery. The human protein DnaJ homologue subfamily A member 1 (DNAJA1) was previously shown to be downregulated 5-fold in pancreatic cancer cells and has been targeted as a biomarker for pancreatic cancer, but little is known about the specific biological function for DNAJA1 or the other members of the DnaJ family encoded in the human genome. Our results suggest the overexpression of DNAJA1 suppresses the stress response capabilities of the oncogenic transcription factor, c-Jun, and results in the diminution of cell survival. DNAJA1 likely activates a DnaK protein by forming a complex that suppresses the JNK pathway, the hyperphosphorylation of c-Jun, and the anti-apoptosis state found in pancreatic cancer cells. A high-quality nuclear magnetic resonance solution structure of the J-domain of DNAJA1 combined with a bioinformatics analysis and a ligand affinity screen identifies a potential DnaK binding site, which is also predicted to overlap with an inhibitory binding site, suggesting DNAJA1 activity is highly regulated.
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DOI：
10.1007/s10969-010-9084-9
发表时间：
2010-03
期刊：
Journal of structural and functional genomics
影响因子：
--
作者：
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通讯作者：
Wassenaar, Tsjerk A
影响因子：
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DOI：
10.1016/j.jmr.2011.08.003
发表时间：
2011-12-01
期刊：
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影响因子：
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作者：
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通讯作者：
Bax, Ad
影响因子：
3.7
作者：
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