TAILIEUCHUNG - Báo cáo khoa học: Overexpression of human histone methylase MLL1 upon exposure to a food contaminant mycotoxin, deoxynivalenol

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 onMLLgene regulation, we treated human cells with a common food contaminant mycotoxin, deoxynivalenol (DON). | ỊFEBS Journal Overexpression of human histone methylase MLL1 upon exposure to a food contaminant mycotoxin deoxynivalenol Khairul I. Ansari1 Imran Hussain1 Hriday K. Das2 and Subhrangsu S. Mandal1 1 Department of Chemistry and Biochemistry The University of Texas at Arlington TX USA 2 Pharmacology Neuroscience University of North Texas Health Science Center Fort Worth TX USA Keywords deoxynivalenol mixed lineage leukemia MLL mycotoxin Sp1 Correspondence S. S. Mandal Department of Chemistry and Biochemistry The University of Texas at Arlington Arlington TX 76019 USA Fax 1 817 272 3808 Tel 1 817 272 3804 E-mail smandal@ Received 2 February 2009 revised 29 March 2009 accepted 7 April 2009 doi 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. Elucidating the regulatory network of proto-oncogenes in normal healthy cells and under toxic stress is important for understanding the mechanism of human diseases 1-5 . Mixed lineage leukemias MLLs are a set of evolutionary conserved genes

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