Department of Gastroenterology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
BMC Mol Biol. 2010 Jan 15;11:4. doi: 10.1186/1471-2199-11-4.
Aberrant activation of protein kinases is one of the essential oncogenic driving forces inherent to the process of tumorigenesis. The protein kinase CK2 plays an important role in diverse biological processes, including cell growth and proliferation as well as in the governing and transduction of prosurvival signals. Increased expression of CK2 is a hallmark of some cancers, hence its antiapoptotic properties may be relevant to cancer onset. Thus, the designing and synthesis of the CK2 inhibitors has become an important pursuit in the search for cancer therapies.
Using a high-throughput microarray approach, we demonstrate that two potent inhibitors of CK2, 4,5,6,7-tetrabromo-benzimidazole (TBBz) and 2-Dimethyloamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), blocked mitogen induced mRNA expression of immediate early genes. Given the impact of these inhibitors on the process of transcription, we investigated their effects on RNA Polymerase II (RNAPII) elongation along the mitogen inducible gene, EGR1 (early growth response 1), using chromatin immunoprecipitation (ChIP) assay. ChIP analysis demonstrated that both drugs arrest RNAPII elongation. Finally, we show that CDK9 kinase activity, essential for the triggering of RNAPII elongation, was blocked by TBBz and to lesser degree by DMAT.
Our approach revealed that small molecules derived from halogenated imidazole compounds may decrease cell proliferation, in part, by inhibiting pathways that regulate transcription elongation.
蛋白激酶的异常激活是肿瘤发生过程中固有的致癌驱动因素之一。蛋白激酶 CK2 在多种生物学过程中发挥重要作用，包括细胞生长和增殖，以及生存信号的调节和转导。CK2 的表达增加是一些癌症的标志，因此其抗凋亡特性可能与癌症的发生有关。因此，设计和合成 CK2 抑制剂已成为寻找癌症治疗方法的重要目标。
我们使用高通量微阵列方法证明，两种有效的 CK2 抑制剂，4,5,6,7-四溴苯并咪唑（TBBz）和 2-二甲氨基-4,5,6,7-四溴-1H-苯并咪唑（DMAT），阻断有丝分裂原诱导的即时早期基因的 mRNA 表达。鉴于这些抑制剂对转录过程的影响，我们使用染色质免疫沉淀（ChIP）分析研究了它们对有丝分裂原诱导基因 EGR1（早期生长反应 1）上的 RNA 聚合酶 II（RNAPII）延伸的影响。ChIP 分析表明，这两种药物都能阻止 RNAPII 延伸。最后，我们表明 CDK9 激酶活性，对于 RNAPII 延伸的触发是必需的，被 TBBz 抑制，而 DMAT 的抑制作用较小。
我们的方法表明，来源于卤化咪唑化合物的小分子可能通过抑制调节转录延伸的途径来降低细胞增殖，在部分程度上。
