Endothelial cells express a novel, tumor necrosis factor-alpha-regulated variant of HOXA9

The expression of the class 1 homeobox (HOX) family of "master control" tra nscription factors has been studied principally in embryogenesis and neopla sia in which HOX genes play a critical role in cell proliferation, migratio n, and differentiation. We wished to test whether HOX family members were a lso involved in a differentiation-like process occurring in normal, diploid adult cells, that is, cytokine-induced activation of endothelial cells (EC ). Screening of a human EC cDNA library yielded several members of the A ad d B groups of HOX transcription factors. One clone represented a novel, alt ernatively spliced variant of the human HOXA9 gene containing a new exon an d the expression of which was driven by a novel promoter. This variant term ed HOXA9EC appeared restricted to cells of endothelial lineage, i.e. expres sed by human EC from multiple sources, but not by fibroblasts, smooth muscl e cells, or several transformed cell lines. HOXA9EC mRNA was rapidly down-r egulated in EC in response to tumor necrosis factor-alpha due to an apparen t reduction in transcriptional rate. Reporter construct studies showed that the 400 base pairs of genomic DNA directly 5' to the transcription initiat ion site of HOXA9EC contained the information required for both up-regulati on in response to cotransfection with a HOXA9EC expression vector and tumor necrosis factor-alpha-dependent down-regulation of this gene. These result s provide evidence of a novel HOX family member that may participate in eit her the suppression or the genesis of EC activation.