This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phelan, M L Articles by Featherstone, M S Search for Related Content PubMed PubMed Citation Articles by Phelan, M L Articles by Featherstone, M S

Functional differences between HOX proteins conferred by two residues in the homeodomain N-terminal arm.

McGill Cancer Centre, McGill University, Montréal, Québec, Canada.

ABSTRACT

Hox genes encode homeodomain-containing transcriptional regulators that function during development to specify positional identity along embryonic axes. The homeodomain is composed of a flexible N-terminal arm and three alpha helices, and it differentially binds DNA. A number of homeodomains recognize sites containing a TAAT core motif. The product of the murine Hoxd-4 (Hox-4.2) gene functions in a positive autoregulatory fashion in P19 cells that is dependent on two TAAT motifs in the Hoxd-4 promoter. This effect is specific in that murine HOXA-1 (HOX-1.6) is unable to activate transcription through the Hoxd-4 autoregulatory element. Here we show that this is due to an inability of the HOXA-1 homeodomain to bind a HOXD-4 recognition site effectively. We have produced chimeras between HOXD-4 and HOXA-1 to map specific residues responsible for this functional difference. When positions 2 and 3 in the N-terminal arm of HOXA-1 were converted to HOXD-4 identity, both strong DNA binding and transcriptional activation were rescued. This substitution appears to confer an increased DNA-binding ability on the HOXA-1 homeodomain, since we were unable to detect a high-affinity recognition sequence for HOXA-1 in a randomized pool of DNA probes. The contribution of position 3 to DNA binding has been implicated by structural studies, but this is the first report of the importance of position 2 in regulating homeodomain-DNA interactions. Additionally, specific homeodomain residues that confer major differences in DNA binding and transcriptional activation between Hox gene products have not been previously determined. Identity at these two positions is generally conserved among paralogs but varies between Hox gene subfamilies. As a result, these residues may be important for the regulation of target gene expression by specific Hox products.

This article has been cited by other articles:

• Morgan, R., Pirard, P. M., Shears, L., Sohal, J., Pettengell, R., Pandha, H. S. (2007). Antagonism of HOX/PBX Dimer Formation Blocks the In vivo Proliferation of Melanoma. Cancer Res. 67: 5806-5813 [Abstract] [Full Text]  
• Knosp, W. M., Saneyoshi, C., Shou, S., Bachinger, H. P., Stadler, H. S. (2007). Elucidation, Quantitative Refinement, and in Vivo Utilization of the HOXA13 DNA Binding Site. J. Biol. Chem. 282: 6843-6853 [Abstract] [Full Text]  
• Remacle, S., Shaw-Jackson, C., Matis, C., Lampe, X., Picard, J., Rezsohazy, R. (2002). Changing homeodomain residues 2 and 3 of Hoxa1 alters its activity in a cell-type and enhancer dependent manner. Nucleic Acids Res 30: 2663-2668 [Abstract] [Full Text]  
• Ryoo, H. D., Mann, R. S. (1999). The control of trunk Hox specificity and activity by Extradenticle. Genes Dev. 13: 1704-1716 [Abstract] [Full Text]  
• Shen, W.-F., Rozenfeld, S., Kwong, A., Komuves, L. G., Lawrence, H. J., Largman, C. (1999). HOXA9 Forms Triple Complexes with PBX2 and MEIS1 in Myeloid Cells. Mol. Cell. Biol. 19: 3051-3061 [Abstract] [Full Text]  
• Schwartz, P. T., Vallejo, M. (1998). Differential Regulation of Basal and Cyclic Adenosine 3',5'-Monophosphate-Induced Somatostatin Gene Transcription in Neural Cells by DNA Control Elements That Bind Homeodomain Proteins. Mol. Endocrinol. 12: 1280-1293 [Abstract] [Full Text]  
• Green, N. C., Rambaldi, I., Teakles, J., Featherstone, M. S. (1998). A Conserved C-terminal Domain in PBX Increases DNA Binding by the PBX Homeodomain and Is Not a Primary Site of Contact for the YPWM Motif of HOXA1. J. Biol. Chem. 273: 13273-13279 [Abstract] [Full Text]  
• Phelan, M. L., Featherstone, M. S. (1997). Distinct HOX N-terminal Arm Residues Are Responsible for Specificity of DNA Recognition by HOX Monomers and HOX·PBX Heterodimers. J. Biol. Chem. 272: 8635-8643 [Abstract] [Full Text]