Regulation of the intracellular localization of the transcription factor Ets1 (IRM10P.754)

Abstract

Abstract Ets1 is a DNA binding transcription factor that regulates B and T cell responses. To activate transcription Ets1 must be present in the nucleus of the cell. The major isoform of Ets1 (designated p54) has both a nuclear localization signal (NLS) and a nuclear export signal (NES). We have identified a novel isoform of Ets1 (p68) having an alternate N-terminus with 71 distinct amino acids that replace the first 28 amino acids of p54. Unexpectedly, we found that transfected p68 is localized in the cytoplasm of cells, rather than the nucleus where p54 is found, despite the fact that p68 contains both the NLS and NES sequences of Ets1. This suggests that sequences in the first 28 amino acids of p54 Ets1 regulate its nuclear localization. Contained within this region of p54 Ets1 is a lysine residue (K15) known to undergo sumoylation. We made point mutations in this site (to either alanine or arginine) and showed that this residue is essential for nuclear localization of Ets1. Studies are currently underway to determine whether sumoylation of Ets1 is required for its nuclear localization. Interestingly, there may be a conserved mechanism that regulates nuclear localization of Ets proteins. This interpretation is based on our observation that another Ets family member Elf5 also requires an intact N-terminus to be localized within the nucleus of the cell. Our studies predict that nuclear localization of Ets proteins may be a regulated event and under the control of signaling pathways.