Sam68 directs NF‐kB for IL2RA gene transcription

Abstract

The inherent complexity of the recognition of kB sites by transcription factor NF‐kB was underscored by our recent study demonstrating ribosomal protein S3 (RPS3), an essential non‐Rel NF‐kB subunit cooperates with Rel subunits to achieve full binding and transcriptional activity of NF‐kB. RPS3 preferentially directs binding to kB sites of certain NF‐kB genes, thus functioning as a “specifier” subunit. To explore the RPS3‐like “specifier” molecules in the NF‐kB complexes with different gene activation specificities, we identified the Src‐Associated substrate during mitosis of 68kDa (Sam68) as the “specifier” subunit of NF‐kB conferring the specific transcription of IL2RA, a RPS3‐independent gene encoding IL2 receptor alpha chain with important function in hematopoietic cells and high expression in cancers. Sam68 was not detected in the cytoplasmic IkB‐p65 complex in resting T cells, but nuclearly complexed with p65 after stimulation, where it synergistically enhanced NF‐kB complex binding to IL2RA kB site. The significance of Sam68‐conferred recognition was highlighted by the observations that Sam68 knockdown dramatically impaired TCR engagement‐induced IL2Ra upregulation and killed IL2Ra highly expressed cancer cells. Our discovery thus sheds new light on the long‐standing question of NF‐kB regulatory specificity. This research was supported by the NIH, NIAID Intramural Research Program.