Ansari Khairul I, Hussain Imran, Das Hriday K, Mandal Subhrangsu S
Department of Chemistry and Biochemistry, The University of Texas at Arlington, TX 76019, USA.
FEBS J. 2009 Jun;276(12):3299-307. doi: 10.1111/j.1742-4658.2009.07055.x. Epub 2009 May 5.
Mixed lineage leukemias (MLLs) are histone-methylating enzymes with critical roles in gene expression, epigenetics and cancer. Although MLLs are important gene regulators little is known about their own regulation. Herein, to understand the effects of toxic stress on MLL gene regulation, we treated human cells with a common food contaminant mycotoxin, deoxynivalenol (DON). Our results demonstrate that MLLs and Hox genes are overexpressed upon exposure to DON. Studies using specific inhibitors demonstrated that Src kinase families are involved in upstream events in DON-mediated upregulation of MLL1. Sequence analysis demonstrated that the MLL1 promoter contains multiple Sp1-binding sites and importantly, the binding of Sp1 is enriched in the MLL1 promoter upon exposure to DON. Moreover, antisense-mediated knockdown of Sp1 diminished DON-induced MLL1 upregulation. These results demonstrated that MLL1 gene expression is sensitive to toxic stress and Sp1 plays crucial roles in the stress-induced upregulation of MLL1.
混合谱系白血病（MLL）是在基因表达、表观遗传学和癌症中起关键作用的组蛋白甲基化酶。尽管MLL是重要的基因调节因子，但其自身的调节机制却鲜为人知。在此，为了了解毒性应激对MLL基因调节的影响，我们用一种常见的食品污染物霉菌毒素脱氧雪腐镰刀菌烯醇（DON）处理人类细胞。我们的结果表明，暴露于DON后，MLL和Hox基因会过度表达。使用特异性抑制剂的研究表明，Src激酶家族参与了DON介导的MLL1上调的上游事件。序列分析表明，MLL1启动子包含多个Sp1结合位点，重要的是，暴露于DON后，Sp1的结合在MLL1启动子中富集。此外，反义介导的Sp1敲低减少了DON诱导的MLL1上调。这些结果表明，MLL1基因表达对毒性应激敏感，Sp1在应激诱导的MLL1上调中起关键作用。
