Discovery of mechanism for maintaining undifferentiation of mammal ES cells
An Osaka University group led by Professor Yoshihiro YONEDA * and Researcher Noriko YASUHARA * and a Nihon University group led by Professor Hiroko KANEKO * and Researcher Ryosuke YAMAGISHI * through analysis of mice embryonic stem cells (ESCs) and of computational methods in structural biology, made partial clarification of the mechanism by which importin α2, a transport receptor responsible for transporting protein to animal cell nuclei, maintains undifferentiation in mammal ES cells.
Importin α is an export factor for transporting proteins into the cell nuclei of eukaryotic organisms and is involved in transport of transcription factors and important proteins into nuclei. It has been known that importin α2 is frequently expressed in undifferentiated ES cells. It has also been known that importin α2 bound to nuclear localization signal (NLS) in Oct3/4 proteins necessary for initialization, thereby helping their transport into nuclei.
These groups jointly discovered that there was an unknown NLS binding site in importin α2 and that at this site, it bound to specific transcription factor such as Oct6 to promote differentiation, selectively inhibiting transportation. In fact, this joint group clarified for the first time that importin α2 had multiple binding sites and not only promoted transport of transcription factors for maintaining undifferentiation, but also suppressed cell differentiation by preventing intranuclear trafficking of transcription factors inducing cell differentiation.
*Please refer to the full report on their research in the journal Developmental Cell for affiliations. Furthermore, please note that during this research and through its completion, Professor Yoneda was affiliated with two Osaka University graduate schools, Frontier Biosciences and Medicine.
Abstract
We recently demonstrated that the expression of the importin α subtype is switched from α2 to α1 during neural differentiation in mouse embryonic stem cells (ESCs) and that this switching has a major impact on cell differentiation. In this study, we report a cell-fate determination mechanism in which importin α2 negatively regulates the nuclear import of certain transcription factors to maintain ESC properties. The nuclear import of Oct6 and Brn2 was inhibited via the formation of a transport-incompetent complex of the cargo bound to a nuclear localization signal binding site in importin α2. Unless this dominant-negative effect was downregulated upon ESC differentiation, inappropriate cell death was induced. We propose that although certain transcription factors are necessary for differentiation in ESCs, these factors are retained in the cytoplasm by importin α2, thereby preventing transcription factor activity in the nucleus until the cells undergo differentiation.
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To learn more about this research, please read the full research report entitled " Importin Alpha Subtypes Determine Differential Transcription Factor Localization in Embryonic Stem Cells Maintenance " at the journal Developmental Cell .
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