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The Role of the Leukemia Inhibitory Factor (LIF) - Pathway in Derivation and Maintenance of Murine Pluripotent Stem Cells.

Graf U, Casanova EA, Cinelli P - Genes (Basel) (2011)

Bottom Line: STAT3 is known to inhibit differentiation into both mesoderm and endoderm lineages by preventing the activation of lineage-specific differentiation programs.However, LIF activates also parallel circuitries like the PI3K-pathway and the MEK/ERK-pathway, but its mechanisms of action remain to be better elucidated.This review article aims at summarizing the actual knowledge on the importance of LIF in the maintenance of pluripotency and self-renewal in embryonic and induced pluripotent stem cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Animal Science, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. urs.graf@access.uzh.ch.

ABSTRACT
Developmental biology, regenerative medicine and cancer biology are more and more interested in understanding the molecular mechanisms controlling pluripotency and self-renewal in stem cells. Pluripotency is maintained by a synergistic interplay between extrinsic stimuli and intrinsic circuitries, which allow sustainment of the undifferentiated and self-renewing state. Nevertheless, even though a lot of efforts have been made in the past years, the precise mechanisms regulating these processes remain unclear. One of the key extrinsic factors is leukemia inhibitory factor (LIF) that is largely used for the cultivation and derivation of mouse embryonic and induced pluripotent stem cells. LIF acts through the LIFR/gp130 receptor and activates STAT3, an important regulator of mouse embryonic stem cell self-renewal. STAT3 is known to inhibit differentiation into both mesoderm and endoderm lineages by preventing the activation of lineage-specific differentiation programs. However, LIF activates also parallel circuitries like the PI3K-pathway and the MEK/ERK-pathway, but its mechanisms of action remain to be better elucidated. This review article aims at summarizing the actual knowledge on the importance of LIF in the maintenance of pluripotency and self-renewal in embryonic and induced pluripotent stem cells.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the LIF-pathway.
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f1-genes-02-00280: Schematic representation of the LIF-pathway.

Mentions: The Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway mediates the transmission of information received from extracellular polypeptide signals, through transmembrane receptors and directly targets gene promoters without needing second messengers. Leukemia inhibitory factor (LIF) belongs to the family of interleukin (IL)-6-type cytokines, which signal through the common receptor subunit gp130 in association with a ligand-specific receptor subunit, the low-affinity LIF receptor (LIFR). The binding of LIF to the LIFR induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated Janus kinases (JAKs), in the phosphorylation of receptor docking sites, and finally in the recruitment of Src homology-2 (SH2) domain containing proteins such as STAT3 (signal transducer and activator of transcription 3). When bound to the receptor, STAT3 molecules are phosphorylated on tyrosine 705 (Tyr705) residues and dimerize with another phosphorylated STAT3. The dimers are then translocated to the nucleus in a regulated manner where they bind to promoters and enhancer regions of their target genes (Figure 1). The suppressor of cytokine signaling 3 (SOCS3) is an important negative regulator of the LIF/STAT3-pathway whose expression is directly driven by STAT3. SOCS3 plays a critical role in many cell types and tissues in which the LIF-pathway is active.


The Role of the Leukemia Inhibitory Factor (LIF) - Pathway in Derivation and Maintenance of Murine Pluripotent Stem Cells.

Graf U, Casanova EA, Cinelli P - Genes (Basel) (2011)

Schematic representation of the LIF-pathway.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924847&req=5

f1-genes-02-00280: Schematic representation of the LIF-pathway.
Mentions: The Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway mediates the transmission of information received from extracellular polypeptide signals, through transmembrane receptors and directly targets gene promoters without needing second messengers. Leukemia inhibitory factor (LIF) belongs to the family of interleukin (IL)-6-type cytokines, which signal through the common receptor subunit gp130 in association with a ligand-specific receptor subunit, the low-affinity LIF receptor (LIFR). The binding of LIF to the LIFR induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated Janus kinases (JAKs), in the phosphorylation of receptor docking sites, and finally in the recruitment of Src homology-2 (SH2) domain containing proteins such as STAT3 (signal transducer and activator of transcription 3). When bound to the receptor, STAT3 molecules are phosphorylated on tyrosine 705 (Tyr705) residues and dimerize with another phosphorylated STAT3. The dimers are then translocated to the nucleus in a regulated manner where they bind to promoters and enhancer regions of their target genes (Figure 1). The suppressor of cytokine signaling 3 (SOCS3) is an important negative regulator of the LIF/STAT3-pathway whose expression is directly driven by STAT3. SOCS3 plays a critical role in many cell types and tissues in which the LIF-pathway is active.

Bottom Line: STAT3 is known to inhibit differentiation into both mesoderm and endoderm lineages by preventing the activation of lineage-specific differentiation programs.However, LIF activates also parallel circuitries like the PI3K-pathway and the MEK/ERK-pathway, but its mechanisms of action remain to be better elucidated.This review article aims at summarizing the actual knowledge on the importance of LIF in the maintenance of pluripotency and self-renewal in embryonic and induced pluripotent stem cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Animal Science, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. urs.graf@access.uzh.ch.

ABSTRACT
Developmental biology, regenerative medicine and cancer biology are more and more interested in understanding the molecular mechanisms controlling pluripotency and self-renewal in stem cells. Pluripotency is maintained by a synergistic interplay between extrinsic stimuli and intrinsic circuitries, which allow sustainment of the undifferentiated and self-renewing state. Nevertheless, even though a lot of efforts have been made in the past years, the precise mechanisms regulating these processes remain unclear. One of the key extrinsic factors is leukemia inhibitory factor (LIF) that is largely used for the cultivation and derivation of mouse embryonic and induced pluripotent stem cells. LIF acts through the LIFR/gp130 receptor and activates STAT3, an important regulator of mouse embryonic stem cell self-renewal. STAT3 is known to inhibit differentiation into both mesoderm and endoderm lineages by preventing the activation of lineage-specific differentiation programs. However, LIF activates also parallel circuitries like the PI3K-pathway and the MEK/ERK-pathway, but its mechanisms of action remain to be better elucidated. This review article aims at summarizing the actual knowledge on the importance of LIF in the maintenance of pluripotency and self-renewal in embryonic and induced pluripotent stem cells.

No MeSH data available.


Related in: MedlinePlus