Inhibition of C/EBPB by the sesquiterpene lactone helenalinacetate.

Jakobs A, Uttarkar S, Jose J, Müller-Tidow C, Schmidt TJ, Klempnauer K-H

Abstract

The proto-oncogene c-myb encodes a transcription factor (c-Myb) which is highly expressed in progenitor cells of the hematopoietic system, where it regulates the expression of genes involved in the lineage determination, proliferation and differentiation. c-Myb cooperates with C/EBPβ to activate transcription of different myeloid-specific genes1. c-Myb is emerging as an interesting therapeutic target because its deregulation is involved in the development of different types of leukemia and other human tumors2. We have developed a fluorescence-based test system that enables the screening of compounds that have the ability to interfere with the activation of c-Myb target genes3. Using this system to screen the inhibitory activity of sesquiterpene lactones, a class of compounds that are the active components of a variety of medicinal plants4,5, we have identified Helenalinacetate as a new potent inhibitor of the Myb-dependent target gene expression. We have now studied the molecular mechanism underlying its inhibitory mechanism. Our results indicate that the observed inhibition is due to direct inhibition of C/EBPβ. Our compound is the first highly potent inhibitor of C/EBPβ.