Molecules that control the pluripotency in embryonyc stem (ES) and induced pluripotentent stem (iPS) cells and their differentiation

September 27, 2011 (last updated: November 9, 2011)

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It is a well-known fact that several molecules play important roles in the self-renewal and pluripotency of ES cells and iPSCs. These molecules regulate various cells functions such as cell cycle, transcription and so on. Certainly, the elucidation of interactions between these molecules may contribute to understanding the transformations of cells (differentiation and induced pluripotency). Bellow, you can see a list of molecules involved in self-renewal and pluripotency of ES cells and iPSCs. Sure, this list is not complete.

1.   Proteins

1.1 Transcription factors
Master stem cell transcription factors
Nanog - Nanog homeobox               
Oct4 (POU5F1) - POU class5 homeobox1
Sox2 (SRY) -  sex determining region Y-box2

Stem cell transcription factors
CTCF - CCCTC-binding factor (zinc finger protein)

E2f1 - E2F transcription factor1

Esrrb - estrogen-related receptor beta

Gli-like transcription factor Glis1  - Glis family zinc finger1 
HoxB1 - homeobox protein B1
Klf4 - Krüppel-like factor4
c-Myc (c-Myc, v-Myc, MRTL, bHLHe39) and n-Myc. Myelocytomatosis viral oncogene, c-Myc by overexpression activates of TERT, RNA polymerase III, HSP90A, p21, p53. 
Nac1 (NACC1, BTB/POZ domain-containing protein 14B) nucleus accumbens- associated protein 
Neurog1 - neurogenin1
Nkx2-2 - Nk2 homeobox2
Osr2 - protein odd-skipped related2  

Pax6 - paired box6

Pem (now called Rhox5) blocks the in vitro and in vivo differentiation of the cells

REX1 (ZFP42) - acidic zinc-finger protein42
Sall4 - Sal-like protein4
Spic - Spi-C transcription factor

Suz12 - suppresor of zeste 12 homolog (Drosophila)

Tcfcp2l1 - transcription factor CP2-like1
Zfp281 - zinc finger protein281
Zfp36L1 - zinc finger protein 36, C3H type-like1

Zfx - zinc finger protein, X-linked
ZIC3 - zinc finger protein Zic3

1.2   Binding proteins
Lin28  - Lin28 homolog A is a  RNA binding protein
REST - RE1-silencing transcription factor is a RNA binding protein
Rif1 - telomere-associated protein Rif1 is a telomeric DNA binding protein

Id-1 and Id-2 (BMP4/Smad pathway) - DNA binding protein inhibitors Id-1 and Id-2 (or inhibitors of differentiation) that inhibit gene expression in multiple cells

1.3   Cell receptors
bFGFRs (FGF pathway) four basic fibroblast growth factor receptors

Dax1 is nuclear receptor subfamily 0, group B, membre1 
ERRb (ERR2) estrogen related receptor beta

Gpl30 is interleukin 6 receptor-associated signal transducer (LIF-STAT3 pathway)

IGF1R - IGF1 receptor

LIFR (CD118) is leukemia inhibitory factor receptor

Nr5a2 (also known Lrh-1) orphan nuclear receptor that can remplace Oct4 in the derivation of iPSCs from mouse somatic cells

SCF/KitR (SCF/Kit pathway) - stem cell factor and Kit receptor

1.4   Signalling molecules (signal transducer activity)
 The processes involved in maintaining the embryonic state and in generating of induced pluripotent stem cells (iPSCs) are regulated by multiple interactions between cellular signalling molecules. In addition, cell differentiation is coordinated by the same interactions. Signalling molecules belong to several cellular pathways: (1) LIF-STAT3, (2) MAPK-ERK (p42/p44 MAPK), (3) PI3K, (4) Wnt, (5) TGFβ, (6) bFGF and probably others.  
BMP4 (by Smad I/5, TGF-β pathway, BMP4 pathway) - bone morphogenetic protein 4

EGF (EGF pathway) - epidermal growth factor that stimulates cell divisions by induced DNA synthesis (PLC/PKC protein kinase C, Ca2+  influx and ERK1/2 pathway) and by incresed cell metabolism (GLUT1)
bFGF (probably by MAPK signaling, bFGF pathway) basic fibroblast growth factor

DKK1 (Wnt pathway) - dickkopf-related protein1 
FRAT2 (Wnt pathway)  - GSK-3-binding protein

IGFs (IGF pathways) - insulin-like growth factors (IGF1 and IGF2)

IRS1 (IGF pathways) - insulin receptor substrat 1
Lefty/EBAF (TGF-β pathway): Lefty - left-right determination factor and EBAF - endometrial bleeding-associated factor 

NTs - neurotrophins with role in hES cell survival

p53 (TP53 in human or Trp53 in mouse): p53-p21 patway is a barrier in iPSCs generation

SKIL  -  SKI-like oncogene

SMADs (BMP4 pathway) - SMAD family proteins
STAT3  -  signal transducer and activator of transcription 3 (LIF-STAT3  and Wnt-STAT3 pathways may converge c-Myc, Klf4, Pramel7)
TDGF1 (TGF-β pathway) - teratocarcinoma-derived growth factor1 

1.5   Enzymes

AKT or PKB (PI3K pathway) is a serine/treonine protein kinase

ERKs (by LIF) - extracellular signal-regulated kinase
FGF (FGF pathway) - fibroblast growth factor

JAKs (LIF-STAT3 pathway) - Janus-associated tyrosine kinase

MAPK-ERK (MAPK-ERK parhway) - mitogen-activated protein kinase

PI3K (PI3K pathway) - phosphoinositide 3-kinase

Src family kinase (Src family pathway):  Hck, Lck, Lyn, Yes

2.   micro RNA
Let-7 microRNA


 1.         Annerén, C. (2008) Tyrosine kinase signalling in embryonic stem cells. Clinical Science. 115, 43-55.

 2.          Azevedo, JL. and Feldman, RA. (2010) Tinkering with Transcription Factors Uncovers Plasticity of Somatic Cells. Genes Cancer. 1, 1089-99.

 4.          Casanova, EA. et al. (2011) Pramel7 Mediates LIF/STAT3 Dependent Self-Renewal in embryonic Stem Cells. Stem Cells. 29, 474-85.

 5.          Hong, H. et al. (2009) Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature. 460, 1132-35. 

 6.         Kashyap, V. et al. (2009) Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev. 7, 1093-1108. 

 7.         Liu, N. et al. (2006) Molecular mechanisms involved in self-renewal and pluripotency of embryonic stem cells. J Cell Physiol. 211, 279-286.

 8.         Orkin, S.H. et al. (2008) The transcriptional network controlling pluripotency in ES cells. Cold Spring Harb Symp Quant Biol. 73, 195-202.

 9.       Scheper, W. and Copray, S. (2009) The molecular mechanism of induced pluripotency: a two-stage switch. Stem Cell Rev. 5, 204-23.

10.          Teng, SC. et al. Direct activation of HSP90A Transcription by c-Myc Contributes to c-Myc-induced Transformation. J. Biol. Chem. 279, 14649-55.

11.          Wu, KJ. et al. (1999) Direct activation of TERT transcription by c-Myc. Nature Genetics. 21, 220-24.