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Title: {beta}-Catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells

Abstract

It is well known that mouse embryonic stem (ES) cells can be maintained by the presence of leukemia inhibitory factor (LIF). Recent studies have revealed that Wnt also exhibits activity similar to LIF. The molecular mechanism behind the maintenance of ES cells by these factors, however, is not fully understood. In this study, we found that LIF enhances level of nuclear {beta}-catenin, a component of the Wnt signaling pathway. Expression of an activated mutant of {beta}-catenin led to the long-term proliferation of ES cells, even in the absence of LIF. Furthermore, it was found that {beta}-catenin up-regulates Nanog in an Oct-3/4-dependent manner and that {beta}-catenin physically associates with Oct-3/4. These results suggest that up-regulating Nanog through interaction with Oct-3/4 involves {beta}-catenin in the LIF- and Wnt-mediated maintenance of ES cell self-renewal.

Authors:
 [1];  [1];  [2]
  1. Department of Stem Cell Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640 (Japan)
  2. Department of Stem Cell Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640 (Japan). E-mail: hkoide@med.kanazawa-u.ac.jp
Publication Date:
OSTI Identifier:
20979798
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 353; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.12.072; PII: S0006-291X(06)02748-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL PROLIFERATION; LEUKEMIA; LITHIUM FLUORIDES; MICE; MUTANTS; STEM CELLS

Citation Formats

Takao, Yukinari, Yokota, Takashi, and Koide, Hiroshi. {beta}-Catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2006.12.072.
Takao, Yukinari, Yokota, Takashi, & Koide, Hiroshi. {beta}-Catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells. United States. doi:10.1016/j.bbrc.2006.12.072.
Takao, Yukinari, Yokota, Takashi, and Koide, Hiroshi. Fri . "{beta}-Catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells". United States. doi:10.1016/j.bbrc.2006.12.072.
@article{osti_20979798,
title = {{beta}-Catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells},
author = {Takao, Yukinari and Yokota, Takashi and Koide, Hiroshi},
abstractNote = {It is well known that mouse embryonic stem (ES) cells can be maintained by the presence of leukemia inhibitory factor (LIF). Recent studies have revealed that Wnt also exhibits activity similar to LIF. The molecular mechanism behind the maintenance of ES cells by these factors, however, is not fully understood. In this study, we found that LIF enhances level of nuclear {beta}-catenin, a component of the Wnt signaling pathway. Expression of an activated mutant of {beta}-catenin led to the long-term proliferation of ES cells, even in the absence of LIF. Furthermore, it was found that {beta}-catenin up-regulates Nanog in an Oct-3/4-dependent manner and that {beta}-catenin physically associates with Oct-3/4. These results suggest that up-regulating Nanog through interaction with Oct-3/4 involves {beta}-catenin in the LIF- and Wnt-mediated maintenance of ES cell self-renewal.},
doi = {10.1016/j.bbrc.2006.12.072},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 353,
place = {United States},
year = {Fri Feb 16 00:00:00 EST 2007},
month = {Fri Feb 16 00:00:00 EST 2007}
}
  • Mechanical strain has been reported to affect the proliferation/differentiation of many cell types; however, the effects of mechanotransduction on self-renewal as well as pluripotency of embryonic stem (ES) cells remains unknown. To investigate the effects of mechanical strain on mouse ES cell fate, we examined the expression of Nanog, which is an essential regulator of self-renewal and pluripotency as well as Nanog-associated intracellular signaling during uniaxial cyclic mechanical strain. The mouse ES cell line, CCE was plated onto elastic membranes, and we applied 10% strain at 0.17 Hz. The expression of Nanog was reduced during ES cell differentiation in responsemore » to the withdrawal of leukemia inhibitory factor (LIF); however, two days of cyclic mechanical strain attenuated this reduction of Nanog expression. On the other hand, the cyclic mechanical strain promoted PI3K-Akt signaling, which is reported as an upstream of Nanog transcription. The cyclic mechanical strain-induced Akt phosphorylation was blunted by the PI3K inhibitor wortmannin. Furthermore, cytochalasin D, an inhibitor of actin polymerization, also inhibited the mechanical strain-induced increase in phospho-Akt. These findings imply that mechanical force plays a role in regulating Nanog expression in ES cells through the actin cytoskeleton-PI3K-Akt signaling. -- Highlights: Black-Right-Pointing-Pointer The expression of Nanog, which is an essential regulator of 'stemness' was reduced during embryonic stem (ES) cell differentiation. Black-Right-Pointing-Pointer Cyclic mechanical strain attenuated the reduction of Nanog expression. Black-Right-Pointing-Pointer Cyclic mechanical strain promoted PI3K-Akt signaling and mechanical strain-induced Akt phosphorylation was blunted by the PI3K inhibitor and an inhibitor of actin polymerization.« less
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  • Embryonic stem (ES) cells, derived from the inner cell mass of blastocysts, have a characteristic cell cycle with truncated G1 and G2 phases. Recent findings that suppression of Oct3/4 expression results in a reduced proliferation rate of ES cells suggest the involvement of Oct3/4 in the regulation of ES cell growth, although the underlying molecular mechanism remains unclear. In the present study, we identified E2F3a as a direct target gene of Oct3/4 in ES cells. Oct3/4 directly bound to the promoter region of the E2F3a gene and positively regulated expression of E2F3a in mouse ES cells. Suppression of E2F3a activitymore » by E2F6 overexpression led to the reduced proliferation in ES cells, which was relieved by co-expression of E2F3a. Furthermore, cell growth retardation caused by loss of Oct3/4 was rescued by E2F3a expression. These results suggest that Oct3/4 upregulates E2F3a expression to promote ES cell growth. - Highlights: • Oct3/4 positively regulates E2F3a expression in ES cells. • Oct3/4 binds to the promoter region of the E2F3a gene. • Overexpression of E2F6, an inhibitor of E2F3a, reduces ES cell growth. • E2F3a recovers growth retardation of ES cells caused by Oct3/4 reduction.« less
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