Pierre Galka, Patrice Soumillion and René Rezsohazy
Université Catholique de Louvain, Institute of Life Sciences, Belgium
The oncogenic character of protein Pbx1a (PreB-cell leukemia transcription factor 1a) is well established and suggests its implication not only in childhood leukemia but also in numerous other cancers (pancreas, liver, breast or prostate). This ubiquitous implication in cancers together with our bioinformatics analyses showing 100% conservation in mammalian sequences of Pbx1a suggest a hub position of the protein in transcriptional events of normal cell development and cancerogenesis.
Our research project aims at developing a new method for interfering with transcriptional regulation by screening millions of biosynthetic cyclic peptides obtained with an intein-based method.
The principal work hypothesis is that some cyclic peptides in these genetic libraries can act as disruptors of the ternary transcriptional enhancer complex formed between Pbx1a, its cofactor protein Hoxa1 and a specific target DNA sequence (HoxB1-Auto Regulatory Element).
Active peptides screening involve not only their direct activity to interfere with Pbx1a/Hoxa1/HoxB1-ARE transcriptional complex formation but also stability of molecules in physiological conditions and ability to reach intracellular targets and especially to enter the nuclear compartment. So investigated first in bacteria, our project was recently adapted for a eukaryotic host S.cerevisiae, extensively used as model organism for gene regulation investigations. We consider the control of genes expression pattern by PBX1a/ Hoxa1/ARE impairing as the first step in the way for the control of cell proliferation occurring in t(1;19) pre B-ALL due to chimeric Pbx1a-E2A protein and it’s abnormal transcriptional behavior.
Keywords: Transcriptional regulation, anticancer, cyclic peptides.