Leukemia Inhibitory Factor: An Overview

Leukemia Inhibitory Factor and JAK-STAT Signalling Pathway

Leukemia inhibitory factor (LIF) is a cytokine that belongs to the interleukin-6 (IL-6) family of cytokines. Other members of this family include IL- 11, oncostatin M, and ciliary neurotrophic factor (CNTF). LIF was first identified in 1981 as a hematopoietic factor that could stimulate the growth of leukaemia cells in culture. LIF has been shown to be involved in the development, maintenance, and function of various tissues and organs, including the immune system, nervous system, endocrine system, and reproductive system.

Leukemia Inhibitory factor signalling pathway overview

LIF uses the JAK-STAT pathway to signal. LIF binds to the LIF receptor (LIFR), which is a member of the gp130 cytokine receptor family and activates the JAK-STAT signalling pathway. The LIFR protein contains an extracellular domain, a transmembrane domain, and a cytoplasmic domain. The extracellular domain of LIFR binds to LIF, while the cytoplasmic domain contains several tyrosine residues that are involved in signal transduction. This leads to STAT activation and induction of gene transcription. LIF binds to the LIFR, causing it to heterodimerize with gp130. The LIF/LIFR complex activates the Janus kinase (JAK), which phosphorylates receptor docking sites and subsequently recruits Src homology-2 (SH2) domain-containing proteins such as STAT3. The STAT3 molecules are phosphorylated on tyrosine 705 and dimerize with another phosphorylated STAT3. The dimers are escorted to the nucleus in a precise way, where they bind to their target genes' promoters and enhancer regions. The suppression of cytokine signalling 3 (SOCS3) is a crucial negative regulator of the LIF/STAT3 pathway that is directly activated by STAT3. Researchers have found that SOCS3 is essential for a variety of cell types and tissues in which the LIF-pathway is active. The LIF/LIFR complex also recruits SHP-Tyk-Jak proteins, which are negative regulators of the JAK-STAT pathway, and thus limits its activity.

JAK-STAT: Overview

The JAK-STAT (Janus kinase signal transducer and activator of transcription) pathway transmits information received from extracellular polypeptide signals via transmembrane receptors and directly targets gene promoters without the need for second messengers. The JAK/STAT pathway is involved in many important biological processes, including cell growth, differentiation, and apoptosis.

STAT proteins

The STAT proteins are transcription factors that are activated by phosphorylation. Once activated, they translocate to the nucleus and regulate gene expression. In most cases, the STAT proteins act as positive regulators of gene expression. However, they can also act as negative regulators depending on the context. The activation of STAT proteins leads to changes in gene expression that can promote cell growth, survival, and migration. In the context of cancer, these changes can result in tumorigenesis.

JAK proteins

JAK proteins are enzymes that mediate the transmission of signals from cytokines and growth factors to STAT proteins. JAK proteins are named for their ability to phosphorylate the Janus kinase (JAK) domain, which is found in all JAK proteins. The four main members of the JAK family are JAK- tyrosine kinases (JAK-TKs), JAK- non-tyrosine kinases (Jak-Ntk), JNK/SAPKs, and MAPKs.  

Leukaemia Inhibitory Factor and Cancer

LIF signalling through the JAK/STAT pathway has been implicated in the development of several types of cancer, including breast cancer, ovarian cancer, and lung cancer.

In 2011, it was reported that LIF could potently inhibit tumour growth in multiple mouse models of cancer. LIF was shown to decrease the expression of genes that are necessary for cancer cell proliferation, such as cyclin D and c-Myc. Furthermore, LIF was able to increase the expression of genes that promote apoptosis (cell death). In 2012, another study showed that LIF could sensitize cancer cells to chemotherapy drugs. The authors found that LIF could increase the expression of a protein called p53, which is known to play a role in chemosensitivity.

Leukaemia Inhibitory factor and Immunotherapy

LIF has also been studied in the context of immunotherapy. Immunotherapy is a type of treatment that uses the body's own immune system to fight disease. Cancer cells often take advantage of the immune system by evading detection by the immune system or by hijacking the immune response for their own benefit. Immunotherapy aims to restore the ability of the immune system to fight cancer.

Targeting the LIF pathway may be a promising strategy for treating cancer. Drugs that target the LIF pathway are being developed. However, more research is needed to determine how best to target this pathway for cancer treatment.

Leukaemia Inhibitory Factor and Cellular Functions

In addition to its role in cancer, LIF has also been implicated in embryogenesis, cell fate determination, haematopoiesis, neurogenesis, and osteogenesis. LIF is essential for the maintenance of pluripotency in embryonic stem cells. LIF signalling is also required for the differentiation of neural progenitor cells into neurons.

Affects of Leukaemia Inhibitory Factor knockout in mice  

LIF knockout mice have been generated to study the role of LIF in various tissues and organs. LIF knockout mice are embryonic lethal, meaning they die during development. LIF knockout mice also have defects in the central nervous system. These mice have deficits in motor coordination and balance. This may be due to LIF being required for the survival of dopaminergic neurons, a type of neuron that is important for movement control. They also show increased anxiety and depression-like behaviours. LIF is also required for the development of oligodendrocytes, a type of cell that provides myelin insulation for neurons. LIF knockout mice also have defects in reproduction. Male LIF knockout mice are infertile due to a defect in spermatogenesis. Female LIF knockout mice are fertile but show reduced litter size.

Affects of Leukaemia Inhibitory Factor knockout in mice

LIF-deficient mice also have defects in the endocrine system. These mice have decreased levels of certain hormones, including insulin and glucagon. LIF is required for the development and function of pancreatic beta cells, which are important for insulin secretion. In addition, LIF is also required for the differentiation of adrenocorticotropic hormone (ACTH)-producing cells in the anterior pituitary gland. LIF-deficient mice have been found to have defects in the immune system. Furthermore, LIF is required for the development and function of natural killer cells, a type of white blood cell that is important for fighting viral infections and cancer. Finally, LIF is required for the development of T helper type 17 cells (Th17 cells), a type of white blood cell that helps to fight bacterial infections. LIF-deficient mice that are generated using a conditional knockout approach (in which the gene is knocked out in a specific tissue or at a specific time) have been found to be viable. These mice have helped to elucidate the roles of LIF in various tissues and organs.