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Opposing Putative Roles for Canonical and Noncanonical NF kappa B Signaling on the Survival, Proliferation, and Differentiation Potential of Human Embryonic Stem Cells

Lookup NU author(s): Dr Stuart Atkinson, Professor Lyle Armstrong, Professor Derek Mann, Professor Majlinda Lako

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Abstract

The canonical and noncanonical NF kappa B signaling pathways regulate a variety of cellular activities; however, their functions in human embryonic stem cells (hESCs) have not been fully investigated. Expression studies during hESC differentiation indicated a significant increase in the expression of two key components of the canonical NF kappa B pathway (p50 and Ser529 phosphorylated form of p65) as well as a significant reduction in expression of key components of the noncanonical NF kappa B pathway [v-rel reticuloendotheliosis viral oncogene homolog B (RELB), p52, NIK]. Inhibition of canonical NF kappa B resulted in hESC apoptosis, changes in cell cycle distribution, and reduced hESC proliferation. In addition, inhibition of canonical NF kappa B was associated with significant changes in NANOG and OCT4 expression, suppression of differentiation toward all primitive extraembryonic and embryonic lineages with the exception of primitive ectoderm and ectodermal lineages. Inhibition of noncanonical NF kappa B via small interfering RNA-mediated downregulation of RELB resulted in reduced hESC proliferation and opposite changes to expression of key differentiation lineage markers genes when compared with downregulation of canonical NF kappa B. Chromatin immunoprecipitation assays indicated binding of p65 and RELB to regulatory regions of key differentiation marker genes suggesting a direct transcriptional role for both branches of this pathway in hESC. These findings coupled with opposing trends in expression of key components during hESC differentiation, suggests a fine and opposing balance between the two branches of NF kappa B signaling pathways and their involvement in two distinct processes: the canonical pathway regulating hESC differentiation and the noncanonical pathway maintaining hESC pluripotency. STEM CELLS 2010;28:1970-1980


Publication metadata

Author(s): Yang CB, Atkinson SP, Vilella F, Lloret M, Armstrong L, Mann DA, Lako M

Publication type: Article

Publication status: Published

Journal: Stem Cells

Year: 2010

Volume: 28

Issue: 11

Pages: 1970-1980

Print publication date: 18/11/2010

ISSN (print): 1066-5099

ISSN (electronic): 1549-4918

Publisher: AlphaMed Press, Inc.

URL: http://dx.doi.org/10.1002/stem.528

DOI: 10.1002/stem.528


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