THE p65 SUBUNIT OF NF-kappaB FOR THE RADIOSENSITIZATION OF CELLS

摘要

The transcription factor NF-kappaB is activated in response to various stimuli including ionizing radiation. Disruption of NF-kappaB activation by mutant forms of the NF-kappaB inhibitor IkappaB-alpha or by proteasome inhibitors enhances both sensitivity to radiation and radiation-induced apoptosis. The present invention shows that expression of a dominant negative fragment of human p65 (p65DN) leads to down-regulation of both endogenous p65 protein and its mRNA. The dominant negative protein also inhibits radiation-induced NF-kappaB activation by preventing the proteolysis of IkappaB-alpha, resulting in enhancement of cellular radiosensitivity and radiation-induced apoptosis. The region of p65 in the dominant negative fragment is thus a molecular target for disruption of NF-kappaB activation and sensitization of tumors to radiotherapy.