THE N-TERMINAL PROPIECE OF INTERLEUKIN-1-ALPHA IS A TRANSFORMING NUCLEAR ONCOPROTEIN

Interleukin 1 alpha (IL-1 alpha) is a pleiotropic cytokine involved in the immune response, inflammatory processes, and hematopoiesis, and a cts as a mitogen for several malignant cell types, including acute leu kemia and Kaposi sarcoma cells, These diverse activities have been exc lusively attributed to the plasma membrane receptor-binding, 17-kDa C- terminal component (mature IL-1 alpha) that results from proteolytic p rocessing of the 31- to 33-kDa precursor protein, No biologic function has been ascribed to the unusually large, 16-kDa N-terminal propiece formed as a result of proteolytic processing of IL-1 alpha, We report that the IL-1 alpha N-terminal propiece is concentrated by means of a nuclear localization sequence within the nuclei of both transfected an d leukemic cell lines. Overexpression of this component in glomerular mesangial cells, a model perivascular myofibroblast cell type capable of IL-1 alpha synthesis and processing, results in malignant transform ation to a spindle cell-type tumor, The functionally bipartite nature of the IL-1 alpha precursor represents a unique combination of the C-t erminal, classical cytokine and an N-terminal nuclear oncoprotein, The se findings suggest that nuclear transport of the IL-1 alpha N-termina l component may represent a critical component in the transformation o f IL-1 alpha-producing cells in the bone marrow or the perivascular ar ea to a malignant phenotype.