Leukemia inhibitory factor, or LIF, is an
interleukin 6 class
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autoc ...
that affects
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.
Function
LIF derives its name from its ability to induce the terminal
differentiation of
myeloid leukemic cells, thus preventing their continued growth. Other properties attributed to the cytokine include: the growth promotion and cell differentiation of different types of target cells, influence on
bone metabolism,
cachexia
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart ...
,
neural development,
embryogenesis and
inflammation.
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
regulated LIF has been shown to facilitate
implantation in the mouse model and possibly in humans. It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.
Binding/activation
LIF binds to the specific LIF
receptor
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
(
LIFR-α) which forms a
heterodimer with a specific subunit common to all members of that family of receptors, the
GP130
Glycoprotein 130 (also known as gp130, IL6ST, IL6R-beta or CD130) is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of the type I cytokine receptor within the IL-6 receptor fam ...
signal transducing subunit. This leads to activation of the
JAK
Jak may refer to:
Places
* Ják, a village in Hungary
People
* Jak Alnwick (born 1993), English football goalkeeper
* Jak Jones (born 1993), Welsh professional snooker player
* Raymond Jackson ("JAK") (1927–1997), UK cartoonist
* Jak Airport (c ...
/
STAT
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
(Janus kinase/
signal transducer
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
and activator of
transcription) and
MAPK (
mitogen
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
activated
protein kinase)
cascades.
Expression
LIF is normally expressed in the
trophectoderm of the developing embryo, with its receptor LIFR expressed throughout the
inner cell mass
The inner cell mass (ICM) or embryoblast (known as the pluriblast in marsupials) is a structure in the early development of an embryo. It is the mass of cells inside the blastocyst that will eventually give rise to the definitive structures of t ...
. As embryonic stem cells are derived from the inner cell mass at the blastocyst stage, removing them from the inner cell mass also removes their source of LIF. Recombinant LIF has been produced in plants by InVitria.
Use in stem cell culture
LIF is often added to stem cell culture media as an alternative to feeder cell culture, due to the limitation that feeder cells present by only producing LIF on their cell surfaces. Feeder cells lacking the LIF
gene do not effectively support stem cells. LIF promotes self-renewal by recruiting signal transducer and activator of transcription 3 (
Stat3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family.
Function
STAT3 is a member of the STAT protein family. In respons ...
). Stat3 is recruited to the activated LIF receptor and phosphorylated by
Janus kinase
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoverie ...
. It bears noting that LIF and Stat3 are not sufficient to inhibit stem cell differentiation, as cells will differentiate upon removal of serum. During the reversibility phase of differentiation from naive pluripotency, it is possible to revert cells back to naive pluripotency through the addition of LIF.
Removal of LIF pushes stem cells toward
differentiation, however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene
Nanog.
LIF is typically added to stem cell culture medium to reduce spontaneous differentiation.
References
Further reading
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External links
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* Source of Recombiant Leukemia Inhibitory Factor (http://www.invitria.com/cell-culture-products-services/leukemia-inhibitory-factor-culture-media.html )
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{{Interleukins
Cytokines
Drugs
Oncology