Disease relevance of Kitl

• In vivo administration of SCF can reverse the macrocytic anemia and locally repair the mast cell deficiency of Sl/Sld mice [1].
• Among the most interesting Sl mutations available for study are those that induce sterility in only one sex [2].
• Cerebral hypoxia and ischemia may stimulate neurogenesis through trophic factors, including SCF [3].
• The influence of 3,4-epoxybutene (EB), the primary metabolite of 1,3-butadiene, on the colony-forming response of hematopoietic progenitor cells (HPCs) from C57BL/6, Sl, and W mice was investigated in order to elucidate the role of altered HPC regulation in the pathogenesis of 1,3-butadiene toxicity [4].
• In the present study, we have addressed the mechanism of synergistic growth activation, at the cellular level, by SF and GM-CSF using the blast cells of acute myeloblastic leukemia (AML blasts) [5].

Psychiatry related information on Kitl

• These data suggest that interaction of SCF with the c-kit receptor affects the homing behavior of hematopoietic progenitor cells in the adult animal [6].
• We demonstrate that survival of a melanogenic subpopulation of cultured murine crest cells requires SLF for a critical period, which begins only after the second day of dispersal in vitro [7].
• Genetically engineered mice lacking HGF/SF die in utero due to a failure of placental and hepatocyte differentiation, but little information exists regarding the expression of this signaling system in human development [8].
• The altered AChE glycosylation was due to an increase in a minor AChE isoform, which did not bind Con A, similar to that previously observed to be increased in Alzheimer's disease brain and cerebrospinal fluid [9].
• It has previously been shown that immunization with pathogenic anti-DNA idiotypes (Ids; e.g. 16/6 Id) leads to the induction of experimental system lupus erythematosus (SLF) in naive mice [10].

High impact information on Kitl

• Assembly of this SCF complex is regulated by cell-cycle-dependent phosphorylation of NIPA, which restricts substrate ubiquitination activity to interphase [11].
• Kit/SCF signaling and Mitf-dependent transcription are both essential for melanocyte development and pigmentation [12].
• Matrix metalloproteinase-9 (MMP-9), induced in BM cells, releases soluble Kit-ligand (sKitL), permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche [13].
• To examine the function of SCF-induced phosphatidylinositol (PI) 3'-kinase activation in vivo, we employed the Cre-loxP system to mutate the codon for Tyr719, the PI 3'-kinase binding site in Kit/SCF-R, to Phe in the genome of mice by homologous recombination [14].
• Receptor dimerization is ubiquitous to the action of all receptor tyrosine kinases, and in the case of dimeric ligands, such as the stem cell factor (SCF), it was attributed to ligand bivalency [15].

Chemical compound and disease context of Kitl

• Recent reports by several groups that the SI locus encodes a protein known variably as stem cell factor (SCF), mast cell growth factor, or kit ligand, suggests the possibility that the lack of wild-type SCF in SI/SI(d) mice is responsible for their defective response to 5FU-induced thrombocytopenia [16].
• RESULTS: Macrophages responded to untested and SCF ascites in a dose-dependent fashion, with a multifold increase in both IL-1 beta and TNF-alpha messenger RNA (mRNA) and protein, which was often more potent than lipopolysaccharide [17].
• The G(alpha)i inhibitor, pertussis toxin, significantly diminished PACAP-induced 5-HT release from BMCMCs in SCF suggesting the involvement of heterotrimeric G-proteins [18].
• Previously, we showed that c-kit receptor tyrosine kinase is expressed by a subpopulation of dorsal root ganglion (DRG) neurons, and that the ligand for the c-kit receptor, stem cell factor (SCF), induces the neurite outgrowth and supports the survival of these neurons in culture [16] [19].
• Splenocytes or macrophages were obtained from endotoxemia and endotoxin tolerance models pretreated with indomethacin, and then cytokine production was induced by Con A-stimulated splenocytes for the Th cytokine assays and LPS-stimulated macrophages for the IL-6 assay [20].

Biological context of Kitl

• We show that Kitl induces telomerase activity in mitotic spermatogonia and increases the mRNA levels of both the catalytic subunit form and the telomerase RNA template [21].
• Seven of the eight ENU-induced Kitl(Sl) alleles, of which five cause missense mutations, one causes a nonsense mutation and exon skipping, and one affects a splice site, were found to contain point mutations in Kitl [22].
• Interestingly, each of the five missense mutations affects residues that are within, or very near, conserved alpha-helical domains of Kitl [22].
• Kit and its ligand, Kitl, function in hematopoiesis, melanogenesis, and gametogenesis [23].
• Recent findings demonstrating that W encodes the c-kit proto-oncogene, a tyrosine kinase membrane receptor, have suggested that Sl encodes a ligand for c-kit [24].

Anatomical context of Kitl

• A specific endoplasmic reticulum export signal drives transport of stem cell factor (Kitl) to the cell surface [25].
• Efficient cell surface presentation of Kitl is essential for the migration, proliferation, and survival of melanocytes, germ cells, hemopoietic stem cells, and mastocytes [25].
• Our data suggest that the induction of telomerase by Kitl may contribute to the self-renewing potential of male germ cells and of PGCs [21].
• Since spermatogonia proliferation is under Kitl control, we explored its possible role in the regulation of telomerase activity [21].
• In the testis, Kitl is expressed by Sertoli cells and Kit is expressed by spermatogonia and Leydig cells [23].

Associations of Kitl with chemical compounds

• Thus the C-terminal valine defines a specific ER export signal in Kitl [25].
• Kitl-stimulated testosterone production was 2-fold higher than that in untreated controls [23].
• By comparing the effects of multiple Kitl mutations, including two N-ethyl-N-nitrosourea-induced hypomorphic mutations, we were able to distinguish stages of PGC development that are preferentially affected by certain mutations [26].
• Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor [1].
• But labelling with bromodeoxyuridine shows that SCF is not, by itself, a mitogen for PGC [27].

Physical interactions of Kitl

• In addition, our current understanding of the molecular basis of various Steel and Dominant Spotting alleles coupled with the emerging information on the expression pattern of steel factor and c-kit transcripts during development, is now beginning to explain the pleiotropic affects of these mutations [28].
• Epo stimulation of BMMCs led to the activation of a DNA-binding activity that comigrated with the SCF-induced band, but peaked and was maintained at later time points than SCF-induced activation [29].
• SCF led to the rapid and transient activation of a DNA-binding factor that was identified by supershift analysis as STAT-5 [29].
• The MGF complexes formed upon initiation of lactation in the mammary gland and upon stimulation of mammary epithelial cells with PRL migrated at the same position in electrophoretic mobility shift assay, whereas the MGF complex found in mammary gland extracts of pregnant mice exhibited a faster mobility [30].
• This finding indicates that MGF regulates the DNA binding activity of YY1 and thereby may cause the relief of transcriptional repression [31].

Regulatory relationships of Kitl

• These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function [32].
• Mouse bone marrow-derived mast cells (BMMCs) developed with interleukin 3 (IL-3) can be stimulated by c-kit ligand (KL) and accessory cytokines over a period of hours for direct delayed prostaglandin (PG) generation or over a period of days to prime for augmented IgE-dependent PG and leukotriene (LT) production, as previously reported [33].
• Thus, the present studies show the potent ability of Tpo to enhance the growth of primitive multipotent murine BM progenitors in combination with multiple early acting cytokines and documents its unique ability to synergize with SCF to enhance Mk production from such progenitors [34].
• Post-transcriptional stabilization by interleukin-1beta of interleukin-6 mRNA induced by c-kit ligand and interleukin-10 in mouse bone marrow-derived mast cells [35].
• By using an in vitro oocytes culture system, we found that oocytes-derived Akt and FKHRL1 are regulated by SCF [36].

Other interactions of Kitl

• We have also provided biological and physical evidence that SCF is a ligand for the c-kit receptor [1].
• Our results are consistent with the conclusion that SLF, Epo, IL-4, and IL-6 are important during the early stages of ES cell differentiation and hematopoietic development [37].
• Both Kit+ and KitA+ isoforms showed increased autophosphorylation and enhanced association with phosphatidylinositol (PI) 3' kinase and PLC gamma 1, when stimulated with recombinant soluble Steel factor [38].
• Furthermore, the combination of SCF with IL-3, but not the other cytokines, exhibited an increase in bone marrow-derived mast cell proliferation [39].
• We have also found that the mast cells generated in colonies stimulated by IL-4, IL-10, and SCF produced high levels of histamine (6-8 pg per cell) [40].

Analytical, diagnostic and therapeutic context of Kitl

• Here we report an in situ hybridization analysis comparing the expression profiles of MGF and c-kit transcripts during mouse embryogenesis [41].
• Flow cytometry showed that, unlike the cells treated with soluble SLF, no downmodulation of cell-surface KIT expression was observed in M07e cells cultured with immobilzed YB5.B8 MoAb [42].
• Studies using micromanipulation and serum-free culture showed that the effects of sTPOR and SF on the primitive progenitors are direct, not mediated by contaminating stromal cells, and not dependent on factors present in the serum [43].
• The presence of membrane-bound SF was detected by immunofluorescence, suggesting the possibility that secreted or membrane-bound SF may, at least in part, contribute to the density-dependent growth of AML blasts [5].
• Moreover, both Sl and W mice responded to the bile duct ligation, similar to the control mice, by developing new bile ducts [44].

References