Distinct effects of importin α2 and α4 on Oct3/4 localization and expression in mouse embryonic stem cells

The cellular repertoire of importin (IMP) proteins that mediates nuclear import of transcription factors and chromatin remodeling agents is critical to processes such as differentiation and transformation. This study identifies for the first time independent roles for specific IMP alpha s in murine embryonic stem cells (mESCs), showing that mESC differentiation is accompanied by dynamic changes in the levels of transcripts encoding the IMPs, IMP alpha 3, IMP alpha 4, IMP beta 1, and IPO5. Of these, only IMP alpha 4 was maintained at higher levels in differentiating mESCs, correlating with the finding that IMP alpha 4 overexpression induced a significant decrease in Oct3/4 protein levels compared to control transfections. In parallel, IMP alpha 4 protein showed a unique and striking shift in subcellular localization from the nucleus to the cytoplasm during differentiation, which is consistent with activation of a role in nuclear import of differentiation factors. Overexpression of a dominant-negative IMP alpha 2 isoform, when assessed against adjacent untransfected or IMP alpha 2 transfected cells, led to both a significant reduction in endogenous Oct3/4 protein levels and inhibition of Oct3/4 nuclear localization, suggesting that IMP alpha 2-mediated delivery of Oct3/4 to the nucleus contributes directly to maintenance of mESC pluripotency. These findings implicate IMP alpha 2 and IMP alpha 4 in specific but distinct roles in the fate choice between pluripotency and commitment to differentiation.-Young, J. C., Major, A. T., Miyamoto, Y., Loveland, K. L., Jans, D. A. Distinct effects of importin alpha 2 and alpha 4 on Oct3/4 localization and expression in mouse embryonic stem cells. FASEB J. 25, 3958-3965 (2011). www.fasebj.org