Meeting Abstract
41.6 Wednesday, Jan. 5 Critical Regulatory Domain of the Abdominal B (AbdB)-like Transcription Factor HoxA-11 NNAMANI, Mauris*; MEILER, Jens; MIZOUE, Laura; WAGNER, Günter; Yale University,Yale Institute for Systems Biology, New Haven, CT ; Center for Structural Biology, Vanderbilt Univ.,Nashville,TN; Center for Structural Biology, Vanderbilt Univ.,Nashville,TN; Yale University,Yale Institute for Systems Biology, New Haven, CT mauris.nnamani@yale.edu
HoxA-11 is a member of a large class of transcription factors called homeobox genes. It is involved in the regulation of placenta development and required for female fertilization. We have recently shown that this gene experienced strong directional selection in the stem lineage of mammals. We also reported that HoxA-11, although a repressor on the decidual prolactin promoter, is converted to an activator when co-expressed with FOXO1A. This switch in transcription regulation was only noticed in HoxA-11 from placental mammals and all the relevant amino acid substitutions are outside the homeodomain. Our goal in this study is to further understand the functional architecture of the HoxA-11 protein in order to understand the functional significance of the derived amino acid residues. Computational structure predictions suggest the existence of a structured domain in the N-terminal part of the HoxA11 protein, which we call MD, and contain 10 of the derived amino acids. To determine the region of HoxA-11 that is necessary for the upregulation of prolactin and the role of MD, we designed various truncation and deletion constructs of the HoxA-11 gene. Here, we show that the HoxA-11/FOXO1A cooperative upregulation of prolactin is mediated through an activation domain and regulatory motif of HoxA-11 within amino acids 66-151. We further identified the minimal region of the activation domain necessary for the observed increase in prolactin gene expression by designing additional C- and N-terminal deletion constructs of the domain. This regulatory region appears to be crucial in the regulation of HoxA-11 transcriptional activity.
