Sox2 expression is regulated by a negative feedback loop in embryonic stem cells that involves AKT signaling and FoxO1

Autor: Erin L. Wuebben, Briana D. Ormsbee Golden, Angie Rizzino
Rok vydání: 2013
Předmět:
Blotting
Western
lcsh:Medicine
FOXO1
Biology
Models
Biological
03 medical and health sciences
Kruppel-Like Factor 4
Mice
0302 clinical medicine
SOX2
stomatognathic system
Animals
Phosphorylation
lcsh:Science
Transcription factor
Protein kinase B
Cells
Cultured
Embryonic Stem Cells
030304 developmental biology
Regulation of gene expression
Feedback
Physiological
0303 health sciences
Multidisciplinary
Activator (genetics)
Forkhead Box Protein O1
Reverse Transcriptase Polymerase Chain Reaction
SOXB1 Transcription Factors
lcsh:R
fungi
Forkhead Transcription Factors
Gene Expression Regulation
KLF4
030220 oncology & carcinogenesis
Doxycycline
embryonic structures
Cancer research
lcsh:Q
sense organs
Ribonucleosides
Stem cell
biological phenomena
cell phenomena
and immunity
Proto-Oncogene Proteins c-akt
Protein Binding
Signal Transduction
Research Article
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 10, p e76345 (2013)
ISSN: 1932-6203
Popis: The self-renewal and pluripotency of embryonic stem cells (ESC) is regulated by a highly integrated network of essential transcription factors, which includes Sox2. Previous studies have shown that elevating Sox2 on its own in mouse ESC induces differentiation and inhibits the expression of endogenous Sox2 at the protein and mRNA level. These findings led us to hypothesize that increases in Sox2 activate a negative feedback loop that inhibits the transcription of the endogenous Sox2 gene. To test this hypothesis, we used i-OSKM-ESC, which elevate Sox2 in conjunction with Oct4, Klf4, and c-Myc when treated with doxycycline (Dox). Elevating the expression of these four transcription factors in i-OSKM-ESC does not induce differentiation, but it represses expression of endogenous Sox2. We determined that increases of Sox2 in i-OSKM-ESC lead to increases in activated AKT and inactivation of FoxO1 (an activator of Sox2), as well as decreases in binding of FoxO1 to the 5'flanking region of Sox2. Importantly, we determined that inhibition of AKT in Dox-treated i-OSKM-ESC leads to re-expression of endogenous Sox2 at the mRNA and protein level and reactivation of FoxO1. These findings argue that AKT signaling is part of the negative feedback loop that helps carefully control the transcription of Sox2 in ESC by modulating the binding of FoxO1 to the Sox2 gene. Collectively, our findings provide new insights into the mechanisms that enable ESC to carefully regulate the levels of Sox2 and retain their stem cell properties.
Databáze: OpenAIRE
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