C-kit Receptor Research Articles

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) acute myeloid leukemia

Acute myeloid leukemia development occurs in a stepwise fashion whereby an original driver mutation is followed by additional mutations. The first type of mutations tends to be in genes encoding members of the epigenetic/transcription regulatory machinery (i.e., RUNX1, DNMT3A, TET2), while the secondary mutations often involve genes encoding members of signaling pathways that cause uncontrolled growth of such cells such as the growth factor receptors c-KIT of FLT3. Patients usually present with both types of mutations, but it is currently unclear how both mutational events shape the epigenome in developing AML cells. To this end we generated an in vitro model of t(8;21) AML by expressing its driver oncoprotein RUNX1-ETO with or without a mutated (N822K) KIT protein. Expression of N822K-c-KIT strongly increases the self-renewal capacity of RUNX1-ETO-expressing cells. Global analysis of gene expression changes and alterations in the epigenome revealed that N822K-c-KIT expression profoundly influences the open chromatin landscape and transcription factor binding. However, our experiments also revealed that double mutant cells still differ from their patient-derived counterparts, highlighting the importance of studying patient cells to obtain a true picture of how gene regulatory networks have been reprogrammed during tumorigenesis.

Gastrointestinal Stromal Tumor – An Overview

AbstractGastrointestinal stromal tumors (GISTs) are rare tumors but are most common mesenchymal tumors of the digestive tract. They are commonly seen in the stomach (60%) and small intestine (30%). GISTs are likely derived from the interstitial cells of Cajal or their stem cell precursors. They are best characterized by computerized tomography and have a specific staining pattern on immunohistochemistry, i.e., C-Kit and DOG-1. The treatment of GIST is based on the risk assessment for relapse, and patients with localized GIST require resection with or without adjuvant imatinib mesylate (IM). Advanced unresectable tumors are usually treated with IM, with a number of further options available for patients post progression on IM. There is an increasing emphasis on identifying C-Kit and platelet-derived growth factor receptor alpha mutations in all patients with GIST, as these are driver mutations with current and future therapeutic implications.

Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors.

It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2nM in GIST-T1 and 26.6, 3.63, and 47.6nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib.

Acute Alcohol Intoxication Impairs Sonic Hedgehog-Gli1 Signaling and Activation of Primitive Hematopoietic Precursor Cells in the Early Stage of Host Response to Bacteremia.

Activation of hematopoietic stem cells [HSCs, lineage(lin)- stem cell growth factor receptor (c-kit)+ stem cell antigen-1(Sca-1)+ , or LKS cells in mice] is critical for initiating the granulopoietic response. This study determined the effect of alcohol exposure on sonic hedgehog (SHH) signaling in the regulation of HSC activation during bacteremia. Acute alcohol intoxication was induced in mice by intraperitoneal (i.p.) injection of 20% alcohol (5g alcohol/kg body weight). Control mice received i.p. saline. Thirty minutes later, mice were intravenously (i.v.) injected with Escherichia coli (E.coli, 1 to 5×107 CFUs/mouse) or saline. SHH expression by lineage-negative bone marrow cells (BMCs) was significantly increased 24hours after E.coli infection. Extracellular signal-regulated kinase 1/2 (ERK1/2)-specificity protein 1 (Sp1) signaling promotes SHH expression. ERK1/2 was markedly activated in BMCs 8hours following E.coli infection. Alcohol suppressed both the activation of ERK1/2 and up-regulation of SHH expression following E.coli infection. E.coli infection up-regulated GLI family zinc finger 1 (Gli1) gene expression by BMCs and increased Gli1 protein content in LKS cells. The extent of Gli1 expression was correlated with the activity of proliferation in LKS cells. Alcohol inhibited up-regulation of Gli1 expression and activation of LKS cells in response to E.coli infection. Alcohol also interrupted the granulopoietic response to bacteremia. These data show that alcohol disrupts SHH-Gli1 signaling and HSC activation in the early stage of the granulopoietic response, which may serve as an important mechanism underlying the impairment of immune defense against bacterial infection in host excessively consuming alcohol.

PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression.

Enhancing cardiomyocyte survival is crucial to blunt deterioration of myocardial structure and function following pathological damage. PIM1 (Proviral Insertion site in Murine leukemia virus (PIM) kinase 1) is a cardioprotective serine threonine kinase that promotes cardiomyocyte survival and antagonizes senescence through multiple concurrent molecular signaling cascades. In hematopoietic stem cells, PIM1 interacts with the receptor tyrosine kinase c-Kit upstream of the ERK (Extracellular signal-Regulated Kinase) and Akt signaling pathways involved in cell proliferation and survival. The relationship between PIM1 and c-Kit activity has not been explored in the myocardial context. This study delineates the interaction between PIM1 and c-Kit leading to enhanced protection of cardiomyocytes from stress. Elevated c-Kit expression is induced in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1. Co-immunoprecipitation and proximity ligation assay reveal protein–protein interaction between PIM1 and c-Kit. Following treatment with Stem Cell Factor, PIM1-overexpressing cardiomyocytes display elevated ERK activity consistent with c-Kit receptor activation. Functionally, elevated c-Kit expression confers enhanced protection against oxidative stress in vitro. This study identifies the mechanistic relationship between PIM1 and c-Kit in cardiomyocytes, demonstrating another facet of cardioprotection regulated by PIM1 kinase.

Pyoderma gangrenosum-like necrotizing panniculitis associated with Imatinib: A case report.

Imatinib mesylate is a small tyrosine kinase inhibitor that targets BCR-ABL, ckit and platelet-derived growth factor receptor. It is prescribed by hematologists for chronic myeloid leukemia and acute lymphoblastic leukemia and by oncologists for Gastrointestinal Stromal Tumors (GIST). Cutaneous reactions to Imatinib are common but their incidence and severity widely varies between patients. A self-limited skin rash is the most common adverse effect but there have been reported cases of patients with maculopapular rash, pigmentary changes, superficial edema and rarer and clinically distinctive features such as lichenoid reactions or psoriasis. We here describe for the first time a case of pyoderma gangrenosum–like necrotizing panniculitis, a rare dermatological condition, after initiating therapy with Imatinib.

Design of antitumor drugs targeting c-kit receptor by a new mixed ligand-structure based method

An important challenge, in the medicinal chemistry field, is the research of novel forceful drugs to overcome tumor-acquired resistance. The c-Kit tyrosine kinase receptor (TKR) represents a suitable target for the carcinogenesis control of gastro-intestinal stromal (GIST), leukemia, and mastocytosis tumors; nevertheless, several hotspot mutations of the protein limit the efficacy of a few clinical administered TKRs inhibitors. In this study, a new in silico protocol based on ligand and structure-based combined method is proposed, with the aim to identify a set of new c-Kit inhibitors able to complex c-Kit mutated proteins. A recent and freely available web-server DRUDIT is used for the ligand-based method. The protocol application allows for identifying a new generation of potential TKR inhibitors, which, in silico, complex the V654A and T670I mutated proteins and potentially overcome resistant mutations (D816H). The structure-based analysis is performed by Induced Fit Docking (IFD) studies. The comparison between the explored ligands and well-known drugs highlights the possibility to overcome tumor-acquired resistance. The best-selected structures (630705 and SML1348) provide valuable binding affinities with the mutated c-Kit forms (respectively T670I and V654A).

Computational Design for the Production of Secretory Recombinant Codon-Optimized Human Stem Cell Factor (SCF) in Chinese Hamster Ovary (CHO) Cells With an Appropriate Signal Peptide: An Intensive In Silico Study

Background: Production of the recombinant proteins in mammalian cells is an important issue with a bio-therapeutic purpose. Numerous efforts have been focused on the improvement of the yields of recombinant proteins, which include optimization of conventional biological processes, selection of appropriate signal peptides, codon optimization, and re-engineering of cells to produce more proteins. Stem cell factor (SCF) is a blood cytokine which activates the c-Kit receptor. This factor is crucial not only for the differentiation of hematopoietic progenitor cells but also for the survival, proliferation, and differentiation of mast cells. Recently, its therapeutic role in several diseases such as Alzheimer’s and myocardial infarction has been investigated. Therefore, the aim of this study was to design a secretory recombinant human SCF with the maximal yield in an appropriate mammalian host cell as Chinese hamster ovary (CHO) cells using the computational studies. Methods: As the first step, computational simulation studies were carried out to design the appropriate signal peptide for the human SCF protein. Codon optimized coding sequence of hSCF was transferred into a eukaryotic expression vector (pBudCE4.1). Recombinant vector (pBudCE4.1/SCF) was transfected into CHO cells and the stably transformed cells were screened and isolated. Subsequently, the expression of SCF was defined by reverse transcription polymerase chain reaction (RT-qPCR) in stably transformed cells. Results: Our bioinformatics studies indicated that Azurocidin signal peptide could be a suitable signal peptide for the production of SCF proteins in the CHO cells. Accordingly, computational studies revealed that the presence of 6×His-tag did not have a significant impact on the three-dimensional structure of the protein. Furthermore, the expression of hSCF was significant in the stable CHO cells. Conclusion: The use of this approach may, therefore, lead to the production of highly efficient recombinant hSCF, which would be feasible for the mass production of this factor for therapeutic purposes.

Diagnosis of Cutaneous Mastocytosis in an Adult Patient: A Case Report

The cutaneous mastocytosis is characterized by infiltration and proliferation of mast cells in the skin with no evidence of extracutaneous involvement. The clinical findings most frequently found are brownish macules or papules slightly elevated, frequently localized in the limbs, chest and abdomen. Mutations in the c-kit receptor (CD117) are frequent and provide the pathophysiology basis of the disease. These mutations allow autophosphorylation of the c-kit receptor and subsequent degranulation of mast cell precipitated with a variety of stimuli, releasing local or systemic cell mediators capable of causing symptoms. Skin lesions occur in both the systemic and the cutaneous form of the disease, though the latter is more frequently seen in children, while most adults with mastocytosis present signs and symptoms of systemic involvement. Although this clinical pattern, we report a rare case of adult-onset cutaneous mastocytosis in a masculine patient of 32 years old. Clinical presentation featured hyperpigmented macules with brownish coloration diffused through the chest and limbs. Skin and bone marrow biopsies and laboratory testing were made and strengthened the diagnosis of cutaneous mastocytosis, a clinical presentation with little similar case reports.

Excess iodine impairs spermatogenesis by inducing oxidative stress and perturbing the blood testis barrier

Approximately 2 billion people worldwide are susceptible to iodine deficiency. Iodine deficiency has largely been tackled by iodine fortification in salt; however indiscriminate use of iodine raises the risk of iodine toxicity. In this study, we aimed to investigate the molecular mechanisms underlying adverse effect of excess iodine on spermatogenesis. Sprague Dawley (SD) rats were orally administered with 0.7 mg potassium iodide (KI)/100 g Bw and 3.5 mg potassium iodide (KI)/100 g Bw for a period of 60 days. This resulted in significant loss of sperm count and motility. Molecular investigations provided evidence for the generation of oxidative stress with high SOD levels, reduced Nrf2, HO-1 and increased NF-kB and Follistatin. Further investigations showed increased apoptosis evidenced by reduced expression of anti-apoptotic (BCL-2, Survivin), increased expression of pro-apoptotic (Bid, Bax) markers, and increased expression of p53 and other modulators/effectors of apoptosis (cytochrome c, cleaved PARP, caspase3 and caspase9). Analysis of the blood testis barrier proteins showed reduced expression of tight junction (JAM-A, Tricellulin), ectoplasmic specialization (Integrin- β1), adherens junction (N-Cadherin, E-cadherin, β-catenin) proteins, and reduced expression of other junction protein coding genes (Claudin1, Claudin 5, Occludin, ZO-1, Testin, Fibronectin, CAR-F). Focal adhesion kinase (FAK) and key regulators of spermatogenesis (c-Kit receptor, androgen receptor) were also parallelly decreased. Further investigation showed reduced expression of germ cell proliferation and differentiation markers (PCNA, Cyclin D1, c-Kit, Cdk-4). These findings collectively explain the loss of spermatogenesis under excess iodine conditions. In conclusion, excess iodine causes loss of spermatogenesis by inducing oxidative stress and disrupting the blood testis barrier and cytoskeleton.

Stem Cell Factor Receptor Immunoexpression in Adolescent Varicocele.

Stem cell factor receptor (c-kit) plays a crucial role in regulating proliferation and survival of germ cells. The aim of this study was to find the correlation between the number of c-kit positive germ cells, testicular asymmetry and histological grade in varicocele affected testis samples of adolescents. Twenty testicular biopsy samples of adolescents affected by varicocele and eight normal control testes were included. The relationship between percentage of testicular asymmetry, number of tubular c-kit positive germ cells and severity of spermatogenic failure was assessed. The mean (SD; median) histological grade for spermatogenic failure in controls was 1.37(0.52; 1), while in the varicocele group, it was 2.70(1.08; 3) (P = .0052). Mean(SD; median) number c-kit positive germ cells in the control group were 20.1(2.52; 20), while in the varicocele group it was 12.35(7.16; 12.5) (P = .0059). Spearman test documented a significant positive correlation between percentage of hypotrophy and histological grade of spermatogenic failure (r = 0.5544 , 95% CI: 0.1345 to 0.8055, P = .0112) but a negative correlation with the number of c-kit positive cells (r = - 0.5871, 95% CI: - 0.8219 to -0.1817, P = .0065). Moreover, a significant negative correlation was found between grade of histological changes and number of c-kit positive germ cells (P < .0001). A significant correlation between hypotrophy, histological lesions and c-kit positive germ cells exists in varicocele testes. This finding suggests a possible role for c-kit in the pathogenesis of germ cell impairment in varicocele. Histological changes and lack of c-kit germ cells were also noted in testes not displaying hypotrophy. We believe that reliable markers should be found as better predictors of testicular function in adolescent with varicocele.

Ginsenoside Rg1 prevents vascular intimal hyperplasia involved by SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes in a rat balloon injury

Ethnopharmacological relevancePanax ginseng C. A. Mey. is a traditional tonic that has been used for thousands of years, and has positive effects on vascular diseases. Ginsenoside Rg1 (GS-Rg1) is one of the active ingredients of Panax ginseng C. A. Mey. and has been shown to have beneficial effects against ischemia/reperfusion injury. Our previously study has found that GS-Rg1 can mobilize bone marrow stem cells and inhibit vascular smooth muscle proliferation and phenotype transformation. However, pharmacological effects and mechanism of GS-Rg1 in inhibiting intimal hyperplasia is still unknown. Aim of the studyThis study was aimed to investigate whether GS-Rg1 prevented vascular intimal hyperplasia, and the involvement of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1 axes. Materials and methodsRats were operated with carotid artery balloon injury. The treatment groups were injected with 4, 8 and 16 mg/kg of GS-Rg1 for 14 days. The degree of intimal hyperplasia was evaluated by histopathological examination. The expression of α-SMA (α-smooth muscle actin) and CD133 were detected by double-label immunofluorescence. Serum levels of SDF-1α, SCF and soluble FKN (sFKN) were detected by enzyme linked immunosorbent assay (ELISA). The protein expressions of SCF, SDF-1α and FKN, as well as the receptors c-kit, CXC chemokine receptor type 4 (CXCR4) and CX3C chemokine receptor type 1 (CX3CR1) were detected by immunochemistry. ResultsGS-Rg1 reduced intimal hyperplasia by evidence of the values of NIA, the ratio of NIA/MA, and the ratio of NIA/IELA and the ratio of NIA/LA, especially in 16 mg/kg group. Furthermore, GS-Rg1 8 mg/kg group and 16 mg/kg group decreased the protein expressions of the SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes in neointima, meanwhile GS-Rg1 8 mg/kg group and 16 mg/kg group also attenuated the expressions of SDF-1α, SCF and sFKN in serum. In addition, the expression of α-SMA and CD133 marked smooth muscle progenitor cells (SMPCs) was decreased after GS-Rg1 treatment. ConclusionsGS-Rg1 has a positive effect on inhibiting vascular intimal hyperplasia, and the underlying mechanism is related to inhibitory expression of SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes.

Mast cells positive to c-kit receptor and to tryptase in normal to cancer pancreatic tissue and the correlation with angiogenesis.

e16502 Background: In the last years published studies demonstrated that mast cells (MCs) contain pro-angiogenic factors associated with tumoral angiogenesis. Tryptase is the most abundant and potent pro-angiogenic substance contained in MCs secretory granules and it can be released in tumour microenvironment. Up to now few data have been published on the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma cancer tissue (PDACT) and adjacent normal tissue (ANT). Methods: In this study MCs density positive to C-Kit receptor (MCDP-C-KitR), MCs density positive to tryptase (MCDPT), MCs area positive to tryptase (MCAPT), angiogenesis in terms of microvascular density (MVD) and endothelial area (EA) were evaluated by immunohistochemistry and image analysis in both PDACT and ANT. All tissue samples were obtained from 45 patients with stage T2-3N0-1M0 (by AJCC for Pancreas Cancer Staging 7th Edition) who had undergone surgery. For each analyzed tissue parameter mean ± standard deviation was evaluated in both PDACT and ANT and differences were evaluated by Student t-test. Each analysed tissue parameter was then correlated each other by Pearson t-test analysis. Results: The mean value ± standard deviation (SD) regarding MCDP-C-KitR, MCDPT, MCAPT, MVD and EA in TT was 14.69±4.57, 13.31± 4,23, 171.41±62,39 µ2, 29.11±7.93, 201.82±70.05 µ2 respectively and the mean value ± SD in ANT was 5.61 ± 2.39, 5.13 ± 2.03, 54.43 ± 16.73 µ2, 11.45 ± 4.96, 67.60 ± 21.96 µ2, respectively. Differences in terms of mean value ± SD between PDACT and ANT were significant for each analyzed tissue biomarker (p ranged from 0,001 to 0,004 by t-test analysis; Table). Data demonstrated that MCDP-C-KitR MCDPT, MCAPT, MVD and EA significantly increased from ANT to PCT. In PCT it was showed a correlation between MCDP-C-KitR and MCDPT (r = 0.87, p = 0.01), MCDP-C-KitR and MVD (r = 0.74, p = 0.02), MCDP-C-KitR and MCAPT (r = 0.81, p = 0.01), MCDPT and MVD (r = 0.72, p = 0.02), MCD-C-KitR and EA (r = 0.73, p = 0.02), MCDPT and MCAPT (r = 0.85, p = 0.01), MCAPT and MVD (r = 0.76, p = 0.02), MCAPT and EA (r = 0.66, p = 0.03), MCDPT and EA (r = 0.69, p = 0.03), MVD and EA (r = 0.82, p = 0.01). Conclusions: Our data suggest that assessed tissue parameters increased from ANT to PDACT and that MCs are associated with angiogenesis in PDACT. On this basis inhibition of MCs by tyrosine kinase inhibitors such as masitinib or inhibition of tryptase by gabexate mesylate may be a novel antiangiogenetic approach in pancreatic cancer therapy.

Investigation of Novel c-Kit-expressing Smooth Muscle Cells in Murine Cecum.

In the gastrointestinal tract musculatures, c-Kit receptor tyrosine kinase is specifically expressed in interstitial cells of Cajal (ICC). ICC are distributed among the smooth muscle cells and are either bipolar or multipolar in shape. Our previous and current study shows that c-Kit-immunopositive smooth muscle cells are present in the murine cecum. Here, we found that c-Kit-expressing smooth muscle cells (named Kit-SM cells) are situated at the submucosal surface of the circular muscle layer. These cells showed smooth muscle actin and myosin immunoreactivities and ultrastructural features such as thick and thin filaments and caveolae. Kit-SM cells also expressed TMEM16A and LRIG1, which are known to be expressed in ICC. Although the functional significance of Kit-SM cells has yet to be revealed, these cells can be considered to have proliferation or differentiation potential in the cecal musculature.

GATA Factor-Mediated Gene Regulation in Human Erythropoiesis.

SummaryErythroid commitment and differentiation are regulated by the coordinated action of a host of transcription factors, including GATA2 and GATA1. Here, we explored GATA-mediated transcriptional regulation through the integrative analysis of gene expression, chromatin modifications, and GATA factors' binding in human multipotent hematopoietic stem/progenitor cells, early erythroid progenitors, and late precursors. A progressive loss of H3K27 acetylation and a diminished usage of active enhancers and super-enhancers were observed during erythroid commitment and differentiation. GATA factors mediate transcriptional changes through a stage-specific interplay with regulatory elements: GATA1 binds different sets of regulatory elements in erythroid progenitors and precursors and controls the transcription of distinct genes during commitment and differentiation. Importantly, our results highlight a pivotal role of promoters in determining the transcriptional program activated upon erythroid differentiation. Finally, we demonstrated that GATA1 binding to a stage-specific super-enhancer sustains the expression of the KIT receptor in human erythroid progenitors.

Stem cell factor is implicated in microenvironmental interactions and cellular dynamics of chronic lymphocytic leukemia.

The inflammatory cytokine stem cell factor (SCF, ligand of c-kit receptor) has been implicated as a pro-oncogenic driver and an adverse prognosticator in several human cancers. Increased SCF levels have recently been reported in a small series of patients with chronic lymphocytic leukemia (CLL), however its precise role in CLL pathophysiology remains elusive. In this study, CLL cells were found to express predominantly the membrane isoform of SCF, which is known to elicit a more robust activation of the c-kit receptor. SCF was significantly overexpressed in CLL cells compared to healthy tonsillar B cells and it correlated with adverse prognostic biomarkers, shorter time-to-first treatment and shorter overall survival. Activation of immune receptors and long-term cell-cell interactions with the mesenchymal stroma led to an elevation of SCF primarily in CLL cases with an adverse prognosis. Contrariwise, suppression of oxidative stress and the BTK inhibitor ibrutinib lowered SCF levels. Interestingly, SCF significantly correlated with mitochondrial dynamics and hypoxia-inducible factor-1a which have previously been linked with clinical aggressiveness in CLL. SCF was able to elicit direct biological effects in CLL cells, affecting redox homeostasis and cell proliferation. Overall, the aberrantly expressed SCF in CLL cells emerges as a key response regulator to microenvironmental stimuli while correlating with poor prognosis. On these grounds, specific targeting of this inflammatory molecule could serve as a novel therapeutic approach in CLL

The c-kit Receptor Tyrosine Kinase Marks Sweet or Umami Sensing T1R3 Positive Adult Taste Cells in Mice

Previous studies have described a number of protein tyrosine kinases (epidermal growth factor receptor, ErbB2, ErbB3, and c-kit) to be expressed in taste bud cells, their innervating nerves, and in developing taste papillae. Immunohistochemical staining of mouse taste buds was performed to characterize the expression patterns of the c-kit receptor in taste. Here we demonstrate that c-kit positive cells are exclusively co-localized with T1R3 (which forms one half of the receptors for sweet and umami taste) in adult taste cells. This implies that c-kit+ cells are primarily taste cells that respond to sweet and umami, but not to bitter, sour, or salty. These data indicate that the control of c-kit activation may be important for proper taste bud formation and may aid in the maintenance of this specific mature taste cell subpopulation. Further characterization of the functional role of c-kit in taste may lead to superior taste cell cultures or organoids, and elucidate mechanisms of taste cell regulation.

Enhanced signaling via ERBB3/PI3K plays a compensatory survival role in pancreatic tumor cells exposed to [neratinib + valproate

The ERBB1/2/4 inhibitor neratinib causes plasma membrane-associated K-RAS to mislocalize into intracellular vesicles; this effect is enhanced by HDAC inhibitors and the combination of [neratinib + sodium valproate] is now a phase I trial (NCT03919292). The present studies were performed to understand resistance mechanisms that evolve following [neratinib + valproate] exposure. Exposure of pancreatic tumor cells to [neratinib + sodium valproate] initially reduced the expression and phosphorylation of ERBB family receptors, c-MET and c-KIT. Following a 24 h drug exposure and a further 24 h culture in drug free conditions, the effects on c-MET, c-KIT and most ERBB family receptors had returned to near baseline levels. However, the expression and phosphorylation of ERBB3 were increased which was associated with elevated AKT T308 phosphorylation. Knock down of ERBB3 significantly enhanced [neratinib + valproate] lethality, which was associated with greater inactivation of AKT, mTOR, p70 S6K and ERK1/2. The PI3Kα/δ inhibitor copanlisib also significantly enhanced killing after [neratinib + valproate] exposure. Copanlisib enhanced [neratinib + valproate] lethality via autophagosome formation and autophagic flux. Our data argue for further in vivo exploration as to whether copanlisib can be safely combined with [neratinib + valproate].

Hair follicle stem cells regulate retinoid metabolism to maintain the self-renewal niche for melanocyte stem cells.

Metabolites are major biological parameters sensed by many cell types in vivo, whether they function as signaling mediators of SC and niche cross talk to regulate tissue regeneration is largely unknown. We show here that deletion of the Notch pathway co-factor RBP-J specifically in mouse HFSCs triggers adjacent McSCs to precociously differentiate in their shared niche. Transcriptome screen and in vivo functional studies revealed that the elevated level of retinoic acid (RA) caused by de-repression of RA metabolic process genes as a result of RBP-J deletion in HFSCs triggers ectopic McSCs differentiation in the niche. Mechanistically the increased level of RA sensitizes McSCs to differentiation signal KIT-ligand by increasing its c-Kit receptor protein level in vivo. Using genetic approach, we further pinpointed HFSCs as the source of KIT-ligand in the niche. We discover that HFSCs regulate the metabolite RA level in vivo to allow self-renewal of neighboring McSCs.

Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients

Background: Mast cells play an essential role in pathology of bronchial asthma. Stem cell factor (SCF) is a major mast cell growth factor, which could be involved in the local increase of mast cell number in the asthmatic airways when bind to its receptor (C-kit). Existing study aimed to evaluate role of gene expression of SCF and their receptor C-kit in development of bronchial asthma in Iraqi population. Methods: present study included 100 patients diagnostic with bronchial asthma (59 females and 41 males) their ages range from 2 to 61 years and 30 healthy individuals (14 females and 16 males) with the same age range as control group DNA extracted from whole blood samples and then subjected to real time PCR for detection of gene expression. Results: current data showed a significant correlation (p0.05) . The optimum cut-off values for gene expression of SCF and C-kit are ≥ 0.55, ≥2.328 respectively since there are associated with a perfect test for predicting asthma. In conclusion: high gene expression of SCF and C-kit associated with increase severity stage of bronchial asthma without treatment and can be reduced by treatment. How to Cite this Article Pubmed Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. 2020; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Web Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic http://www.sysrevpharm.org/?mno=302645230 [Access: March 29, 2021]. doi:10.5530/srp.2020.1.08 AMA (American Medical Association) Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. 2020; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Vancouver/ICMJE Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. (2020), [cited March 29, 2021]; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Harvard Style MUBARK, N. N., AL-MAAMORI, . J. A. & GHALI, . K. H. (2020) Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP, 11 (1), 51-57. doi:10.5530/srp.2020.1.08 Turabian Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. 2020. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic Systematic Reviews in Pharmacy, 11 (1), 51-57. doi:10.5530/srp.2020.1.08 Chicago Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients. Systematic Reviews in Pharmacy 11 (2020), 51-57. doi:10.5530/srp.2020.1.08 MLA (The Modern Language Association) Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients. Systematic Reviews in Pharmacy 11.1 (2020), 51-57. Print. doi:10.5530/srp.2020.1.08 APA (American Psychological Association) Style MUBARK, N. N., AL-MAAMORI, . J. A. & GHALI, . K. H. (2020) Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic Systematic Reviews in Pharmacy, 11 (1), 51-57. doi:10.5530/srp.2020.1.08