CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity

Genes encoding the Phe-Gly (FG) repeat-containing nucleoporins NUP98 and CA N/NUP214 are at the breakpoints of several chromosomal translocations assoc iated with human acute myeloid leukemia (AML), but their role in oncogenesi s is unclear. Here we demonstrate that the NUP98-HOXA9 fusion gene encodes two nuclear oncoproteins with either 19 or 37 NUP98 FG repeats fused to the DNA binding and PBX heterodimerization domains of the transcription factor HOXA9. Both NUP98-HOXA9 chimeras transformed NIH 3T3 fibroblasts, and this transformation required the HOXA9 domains for DNA binding and PBX interact ion. Surprisingly, the FG repeats acted as very potent transactivators of g ene transcription. This NUP98-derived activity is essential for transformat ion and can be replaced by the bona fide transactivation domain of VP16. In terestingly, FG repeat-containing segments derived from the nucleoporins NU P153 and CAN/NUP214 functioned similarly to those from NUP98. We further de monstrate that transactivation by PG repeat-rich segments of NUP98 correlat es with their ability to interact functionally and physically with the tran scriptional coactivators CREB binding protein (CBP) and p300. This finding shows, for the first time, that a translocation-generated fusion protein ap pears to recruit CBP/p300 as an important step of its oncogenic mechanism. Together, our results suggest that NUP98-HOXA9 chimeras are aberrant transc ription factors that deregulate HOX-responsive genes through the transcript ional activation properties of nucleoporin-specific FG repeats that recruit CBP/p300. Indeed, FG repeat-mediated transactivation may be a shared patho genic function of nucleoporins implicated human AML.