Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET

SET, the translocation breakpoint-encoded protein in acute undifferentiated leukemia (AUL), is a 39-kDa nuclear phosphoprotein and has an inhibitory a ctivity for protein phosphatase 2A (PP2A). SET is fused to a putative oncop rotein, CAN/NUP214, in AUL and is thought to play a key role in leukemogene sis by its nuclear localization, protein-protein interactions and PP2A inhi bitory activity. Here, we describe the isolation and characterization of a novel cDNA encoding a protein with 1542 amino-acid residues that specifical ly interacts in a yeast two-hybrid system as well as in human cells with SE T. This new protein, which we name SEB (SET-binding protein), is identified as a 170-kDa protein by immunoprecipitation with a specific antibody and i s localized predominantly in the nucleus. SEB1238-1434 is determined as a S ET-binding region that specifically binds to SET182-223. SEB also has an on coprotein Ski homologous region (amino acids 654-858), six PEST sequences a nd three sequential PPLPPPPP repeats at the C-terminus. SEB mRNA is express ed ubiquitously in all human adult tissues and cells examined. The SEB gene locus is assigned to the chromosome 18q21.1 that contains candidate tumor suppressor genes associated with deletions in cancer and leukemia. Although the function of SEB is not known, we propose that SEB plays a key role in the mechanism of SET-related leukemogenesis and tumorigenesis, perhaps by s uppressing SET function or by regulating the transforming activity of Ski i n the nucleus.