Hypoxia-activated ligand HAL-1/13 is lupus autoantigen Ku80 and mediates lymphoid cell adhesion in vitro

Hypoxia is known to induce extravasation of lymphocytes and leukocytes duri ng ischemic injury and increase the metastatic potential of malignant lymph oid cells. We have recently identified a new adhesion molecule, hypoxia-act ivated ligand-1/13 (HAL-1/13), that mediates the hypoxia-induced increases in lymphocyte and neutrophil adhesion to endothelium and hypoxia-mediated i nvasion of endothelial cell monolayers by tumor cells. In this report, we u sed expression cloning to identify this molecule as the lupus antigen and D NA-dependent protein kinase-associated nuclear protein, Ku80. The HAL-1/13- Ku80 antigen is present on the surface of leukemic and solid tumor cell lin es, including T and B lymphomas, myeloid leukemias, neuroblastoma, rhabdomy osarcoma, and breast carcinoma cells. Transfection and ectopic expression o f HAL-1/13-Ku80 on (murine) NIH/3T3 fibroblasts confers the ability of thes e normally nonadhesive cells to bind to a variety of human lymphoid cell li nes. This adhesion can be specifically blocked by HAL-1/13 or Ku80-neutrali zing antibodies. Loss of expression variants of these transfectants simulta neously lost their adhesive properties toward human lymphoid cells. Hypoxic exposure of tumor cell lines resulted in upregulation of HAL1/13-Ku80 expr ession at the cell surface, mediated by redistribution of the antigen from the nucleus. These studies indicate that the HAL-1/13-Ku80 molecule may med iate, in part, the hypoxia-induced adhesion of lymphocytes, leukocytes, and tumor cells.