ABSTRACT
The c-myb proto-oncogene encodes a transcription factor that is highly expressed in the progenitor cells of the hematopoietic system, where it regulates the expression of genes important for lineage determination, cell proliferation and differentiation. There is strong evidence that deregulation of c-myb expression is involved in the development of human tumors, particularly of certain types of leukemia, and breast and colon cancer. The c-Myb protein is therefore an interesting therapeutic target. Here, we have investigated the potential of natural sesquiterpene lactones (STLs), a class of compounds that are active constituents of a variety of medicinal plants, to suppress Myb-dependent gene expression. We have developed a test system that allows screening of compounds for their ability to interfere with the activation of Myb target genes. Using this assay system, we have identified the STL mexicanin-I as the first cell-permeable, low-molecular-weight inhibitor of Myb-induced gene expression.
Subject(s)
Gene Expression Regulation, Neoplastic/drug effects , Lactones/pharmacology , Proto-Oncogene Proteins c-myb/antagonists & inhibitors , Sesquiterpenes/pharmacology , Acetyltransferases/antagonists & inhibitors , Animals , Cell Line , Cell Proliferation/drug effects , Chickens , Humans , K562 Cells , Leukemia, Myeloid, Acute/drug therapy , Proto-Oncogene MasABSTRACT
Myc, a key regulator of cellular proliferation, differentiation and apoptosis, exerts its biological functions by activating or suppressing the transcription of specific sets of target genes. C/EBP transcription factors play important roles during differentiation of various cell types and have been identified as critical targets for v-Myc- and c-Myc-dependent suppression of myeloid and fat cell differentiation. Here, we have addressed the mechanism by which v-Myc suppresses the activity of C/EBPbeta. We show that v-Myc is recruited to the aminoterminal domain of C/EBPbeta and interferes with the cooperation of C/EBPbeta and the co-activator p300 by preventing C/EBPbeta-induced phosphorylation of p300. We have identified the protein kinase responsible for C/EBPbeta-induced phosphorylation of p300 as homeo-domain interacting protein kinase 2 (HIPK2) and show that v-Myc displaces the kinase from the C/EBPbeta-p300 complex. Overall, our findings that the modulation of the C/EBPbeta-induced phosphorylation of p300 as a new mechanism of transcriptional suppression by v-Myc.
