Biomedical subjects

Yukihiko Kitamura

Publications and source records attributed to Yukihiko Kitamura.

At least 37 records · Page 2Linked to original sources

PubMed2004

Identification of promoter regions involved in cell- and developmental stage-specific osteopontin expression in bone, kidney, placenta, and mammary gland: an analysis of transgenic mice.

UNLABELLED: Cell-specific expression of GFP under the control of different lengths of the osteopontin promoter in transgenic mice identified the positive and negative regulatory regions for respective cell types. The results provide new insights for physiological and pathological expression of the osteopontin gene. INTRODUCTION: Osteopontin (OPN) is a major non-collagenous bone matrix protein that is involved in normal and pathological calcification and is expressed in a tissue-specific manner. To investigate how such tissue-specific OPN gene expression is regulated in vivo, transgenic mice expressing the green fluorescent protein (GFP) reporter gene controlled by different lengths of the OPN promoter were generated. MATERIALS AND METHODS: Cell- and developmental stage-specific osteopontin expression in transgenic mice was examined by Northern blotting, immunoblotting, fluorescence examination, and in situ hybridization and compared with those of OPN. RESULTS AND CONCLUSIONS: The line bearing the -5505 to +14 region of the OPN promoter was shown by Northern blotting and immunoblotting to express GFP in the same cells that express endogenous OPN (osteoblasts, hypertrophic chondrocytes, renal and mammary gland epithelial cells, and granulated metrial gland [GMG] placental cells) at the same stage in development. Thus, the 5.5-kb -5505 to +14 promoter region is sufficient for proper tissue-specific OPN expression. The lines carrying shorter segments of the OPN promoter showed different expression patterns. These patterns revealed a putative cis-acting element in the -5269 to -5263 region that restricts OPN expression to hypertrophic chondrocytes and a mammary gland-specific expressing element and a GMG cell-specific enhancing element in the -5505 to -3156 region. Furthermore, the -3155 to -1576 region seems to contain positive renal epithelial cell- and GMG cell-specific expression motif(s) as well as a negative regulatory element that prevents OPN expression in fibroblasts. Moreover, the -1576 to -910 region seems to contain a positive osteoblast-specific-expressing element. Thus, the 5.5-kb OPN promoter contains multiple cis-acting elements encoding positive and negative cell-specific regulatory systems.

Animals↗

PubMed2003

Clinical implication and prognostic significance of the tumor suppressor TSLC1 gene detected in adenocarcinoma of the lung.

BACKGROUND: Recently, the TSLC1 (tumor suppressor in lung cancer 1) gene has been identified as a novel tumor suppressor in human nonsmall cell lung carcinoma. To the authors' knowledge, the clinical relevance of TSLC1 gene expression has not been studied using patient data and surgical samples. The current study was designed to evaluate whether the TSLC1 gene can serve as a target for the prognostic determination of patients with pulmonary adenocarcinoma. METHODS: A total of 38 patients who were surgically treated for proven primary lung adenocarcinoma were enrolled in the current study. Surgical specimens were examined for TSLC1 protein expression immunohistochemically and by Western blot analysis. The correlation between levels of TSLC1 expression and pathologic characteristics, as well as prognosis, was investigated. RESULTS: All patients underwent a potentially curative resection of their tumor. TSLC1 antigen expression as evaluated by immunohistochemistry was confirmed by immunoblotting. The expression of TSLC1 protein was found to be inversely correlated with advanced disease stage, lymph node involvement, lymphatic permeation, and vascular invasion. The 4-year overall survival rates of patients with a tumor demonstrating high (> 70% positive cells [n = 14 patients]), intermediate (20-70% positive cells [n = 10 patients]), and low (< 20% positive cells [n = 14 patients]) expression of the TSLC1 antigen were 84%, 28%, and 7%, respectively. In addition, the disease-free survival of patients with a tumor that demonstrated a high percentage of TSLC1 protein-positive cells was reported to be significantly better than that of patients with a tumor that showed a low percentage of TSLC1 protein-positive cells. CONCLUSIONS: The loss or reduction of TSLC1 expression in resected lung adenocarcinoma cases was associated with a poor prognosis, indicating that TSLC1 represents a central effector gene for controlling the biologic aggressiveness of the tumor and that it is an essential biomarker for predicting patient prognosis. These data may help to detect those patients at high risk for recurrence who might benefit from additional therapeutic strategies such as adjuvant therapy.

Adenocarcinoma↗

PubMed2003

Toriello-Carey syndrome associated with respiratory failure and non-mechanical ileus.

Toriello-Carey syndrome comprises agenesis of the corpus callosum, telecanthus, small palpebral fissures, Pierre Robin sequence, abnormal ears, and cardiac defects. We report a boy who has some additional findings, including a severe respiratory failure and intestinal dysmotility. The boy died of these two disorders at age 13 months. Histological examination revealed pulmonary immaturity and a defect of smooth muscle cells in the longitudinal muscle coat of the intestinal musculature, both of which might explain some aspects of the pathophysiology of the patient.

Abnormalities, Multiple↗

PubMed2003

Effect of anatomical distribution of mast cells on their defense function against bacterial infections: demonstration using partially mast cell-deficient tg/tg mice.

Mast cells were depleted in the peritoneal cavity of WBB6F1-tg/tg mice that did not express a transcription factor, MITF. When acute bacterial peritonitis was induced in WBB6F1-+/+, WBB6F1-W/Wv, and WBB6F1-tg/tg mice, the proportion of surviving WBB6F1-+/+ mice was significantly higher than that of surviving WBB6F1-W/Wv or WBB6F1-tg/tg mice. The poor survival of WBB6F1-W/Wv and WBB6F1-tg/tg mice was attributed to the deficient influx of neutrophils into the peritoneal cavity. The injection of cultured mast cells (CMCs) derived from WBB6F1-+/+ mice normalized the neutrophil influx and reduced survival rate in WBB6F1-W/Wv mice, but not in WBB6F1-tg/tg mice. This was not attributable to a defect of neutrophils because injection of TNF-alpha increased the neutrophil influx and survival rate in both WBB6F1-W/Wv and WBB6F1-tg/tg mice. Although WBB6F1-+/+ CMCs injection normalized the number of mast cells in both the peritoneal cavity and mesentery of WBB6F1-W/Wv mice, it normalized the number of mast cells only in the peritoneal cavity of WBB6F1-tg/tg mice. Mast cells within the mesentery or mast cells in the vicinity of blood vessels appeared to play an important role against the acute bacterial peritonitis. WBB6F1-tg/tg mice may be useful for studying the effect of anatomical distribution of mast cells on their antiseptic function.

Alleles↗

PubMed2003

Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors.

Mutations of proto-oncogene c-KIT in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. To investigate the effect of Imatinib on various c-KIT mutations found in GISTs, we examined kinase activity of KIT, cell proliferation and tumorigenicity of transfectants with various c-KIT mutations. Murine lymphoid Ba/F3 cells transfected with one of the three types of mutants (KIT(del559-560), KIT(642Glu), and KIT(820Tyr)) or wild-type KIT were used for the experiments. Phosphorylation of KIT, mitogen-activated protein (MAP) and Akt was studied by immunoblotting with or without immunoprecipitation. In vitro studies on cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylcetrazolium bromide colorimetric assay and in vivo tumorigenicity assay using nude mice were also carried out. Imatinib could inhibit the KIT, MAP and Akt phosphorylation of all the transfectants but had a weaker effect on KIT(820Tyr). Imatinib potently inhibited the proliferation of cells transfected with KIT(820Tyr) at the concentration of 10 microM whereas it inhibited the other 3 types at 1 microM. Moreover, Imatinib could inhibit the tumor formation in nude mice transplanted with transfectants. In various types of activating mutant KIT, Imatinib could inhibit the constitutive activation of KIT signal transduction and cell proliferation both in vitro and in vivo although the effect of Imatinib on KIT(820Tyr) was weaker than that on KIT(del559-560) or KIT(642Glu).

Animals↗

PubMed2003

Enhanced expression of Runx2/PEBP2alphaA/CBFA1/AML3 during fracture healing.

The cause of the dramatic increase in expression of the osteopontin gene during fracture healing was studied in a mouse experimental model. Semiquantitative reverse transcription-polymerase chain reaction, Northern blotting, and in situ hybridization analysis showed that the enhanced expression took place prior to callus formation. The change in the expression pattern of collagenous and noncollagenous bone matrix proteins in addition to Ets-1 and Runx2, major transcription factors of osteopontin, were examined and compared to that of osteopontin. Although Ets-1 expression showed no significant change during fracture healing, enhanced expression of Runx2 corresponding to that of osteopontin was observed. Furthermore, in situ hybridization demonstrated that osteopontin-expressing cells also express the Runx2 gene. The results indicated the possibility that Runx2 is a major regulator of osteopontin during fracture healing.

Animals↗

PubMed2003

Difference of osteopontin gene regulation between bone and kidney.

Osteopontin is a sialoprotein that is expressed in various cells. It plays a variety of important roles in cell adhesion, migration, signaling, calcification, and immunity. Its diverse functions indicate that the regulation of osteopontin may also vary extensively among tissues. Although osteopontin promoter has been studied in vitro, in vivo analyses may be more appropriate for elucidating osteopontin's functions. In an attempt to investigate osteopontin gene expression, we generated transgenic mice in which the bacterial beta-galactosidase reporter gene was conjugated downstream of osteopontin promoter. The osteopontin promoter was a mouse -910 bp upstream fragment, which we had previously found functional in 3T3 cells. Among 34 transgenic founders, 13 mice were transgenic, as determined with the polymerase chain reaction. Osteopontin and beta-galactosidase signals were evaluated with in situ hybridization. Among the 13 transgenic mice, 3 were beta-galactosidase-positive. In these transgenic mice, osteopontin signals were observed in bones and kidneys, whereas beta-galactosidase message was detected only in bones. This suggests that the -910 bp osteopontin promoter is active in bones but not in kidneys. These data imply that the promoter region required for osteopontin expression in kidneys may differ from that in bones.

Animals↗

PubMed2003

A truncated isoform of the protein phosphatase 2A B56gamma regulatory subunit may promote genetic instability and cause tumor progression.

F10, a subline of the B16 mouse melanoma cell line, is itself the parent of the more metastatic BL6 line. BL6 cells differ from F10 cells by an alteration of the gene encoding the B56gamma regulatory subunit of protein phosphatase 2A (PP2A), which results in the expression of a truncated variant of the subunit (Deltagamma1). PP2A is involved in regulating the cell-cycle checkpoint and we found that the checkpoint in BL6 cells is aberrant when the Deltagamma1 protein is expressed. That is, although Deltagamma1 protein levels in cultured BL6 cells are low and these cells do not show an altered checkpoint on gamma-irradiation, irradiated footpad BL6 tumor cells show both a marked increase in Deltagamma1 levels and more extensive polyploidy and less apoptosis than F10 cells. These observations were reproduced with Deltagamma1 gene-transfected F10 cells (F10(Deltagamma1)). Deltagamma1 expression and an aberrant checkpoint are also associated with a higher metastatic ability because irradiated F10(Deltagamma1) tumors metastasized much more frequently than F10 tumors, which rarely metastasized whether irradiated or not. Nonirradiated F10(Deltagamma1) tumors, which do not express Deltagamma1 protein, had similarly low rates of metastasis. The greater metastatic ability of irradiated F10(Deltagamma1) tumors also correlated with the acquisition of many more genomic alterations. Thus, it seems that Deltagamma1 expression may damage the checkpoint, which may then allow the acquisition of genetic alterations that promote metastasis. These observations support the notion that mechanisms promoting the genetic instability of tumors could also aid tumor progression from the nonmetastatic to the metastatic state.

3T3 Cells↗

PubMed2003

Localization of the PP2A B56gamma regulatory subunit at the Golgi complex: possible role in vesicle transport and migration.

The BL6 subline was derived from the F10 line, which was derived from the B16 mouse melanoma cell line. BL6 cells are more invasive than F10 cells and differ genetically from F10 cells by an alteration of the gene encoding the B56gamma regulatory subunit of protein phosphatase 2A (PP2A). This alteration results in the transcription of mRNA encoding a truncated variant of the B56gamma1 isoform (Deltagamma1). When F10 cells were stained with a polyclonal antibody that recognizes three B56gamma isoforms, B56gamma1, B56gamma2, and B56gamma3, the immunofluorescent signals co-localized well with the cis-Golgi marker proteins. When BL6 cells were fractionated in a sucrose gradient, B56gamma1 and B56gamma2, but not B56gamma3, were present in the Golgi-enriched fraction. This fraction also contained the catalytic subunit of PP2A. FLAG-tagged Deltagamma1 preferentially localized to the trans-Golgi area rather than the cis-Golgi. This localization was the same as that of FLAG-tagged B56gamma1. NIH3T3 cells stably expressing Deltagamma1 transported a mutant viral protein from the endoplasmic reticulum to the plasma membrane much faster than wild-type cells. Their directional migration, as assessed by the advance of cells into a cell-free area, was also elevated. As Deltagamma1 reduces the activity of the B56gamma-containing PP2A holoenzymes, these results suggest that the normal holoenzymes suppress vesicle transport and that Deltagamma1 might increase the invasive ability of BL6 cells by activating Golgi function.

3T3 Cells↗

PubMed2003

Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors.

BACKGROUND & AIMS: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) alpha, we examined whether GISTs without KIT mutations had a mutation of PDGFR alpha. METHODS: Whole coding region of PDGFR alpha complementary DNA (cDNA) was sequenced in GISTs with or without KIT mutations. Mutant PDGFR alpha cDNA was transfected into 293T human embryonic kidney cells, and autophosphorylation of PDGFR alpha was examined. Proliferation of Ba/F3 murine lymphoid cells stably transfected with mutant PDGFR alpha cDNA was estimated by tritium thymidine incorporation. Wild-type KIT cDNA was cotransfected with mutant PDGFR alpha cDNA, and immunoprecipitation by anti-KIT antibody was performed. Inhibitory effect of Imatinib mesylate on activated PDGFR alpha was examined. RESULTS: We found 2 types of constitutively activated mutations of PDGFR alpha, Val-561 to Asp or Asp-842 to Val, in 5 of 8 GISTs without KIT mutations but not in 10 GISTs with KIT mutations. Stable transfection of each mutation induced autonomous proliferation of Ba/F3 cells. Constitutively activated mutant PDGFR alpha bound and activated the cotransfected wild-type KIT. The constitutive activation of PDGFR alpha with Val-561 to Asp was inhibited effectively by Imatinib mesylate but that of PDGFR alpha with Asp-842 to Val was inhibited only weakly, even at the concentration of 10 micromol/L. CONCLUSIONS: The gain-of-function mutations of PDGFR alpha appear to play an important role in development of GISTs without KIT mutations.

Amino Acid Substitution↗

PubMed2003

The role of the c-kit receptor in the regenerative differentiation of rat Leydig cells.

To determine the physiological role of the c-kit receptor, which is highly expressed in Leydig cells, the regenerative differentiation of Leydig cells was studied following transient degeneration induced by ethane dimethyl sulphonate (EDS) in c-kit-deficient mutant rats (Ws/Ws). EDS caused the destruction of Leydig cells; their functional recovery was evaluated by the weight change of the target organs of androgens, which occurred at the same rate in Ws/Ws and wild-type rats. These results indicate that the tyrosine kinase activity of the c-kit receptor does not play an essential role in the regenerative differentiation of Leydig cells.

Androgens↗

PubMed2003

c-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors.

BACKGROUND AND AIM: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the human gut. They frequently have gain-of-function mutations of the c-kit gene, which encodes a receptor, tyrosine kinase. The mutations were found at exon 11 in most cases, and either at exon 9 or at exon 13 in rare cases. Recently, we found a family with multiple GIST and a gain-of-function mutation at exon 17. The family was the first reported GIST case with c-kit gene mutation at exon 17 including sporadic GIST. Although we previously reported that the c-kit gene mutation at exon 17 was not detected in 124 sporadic GIST by single-strand conformation polymorphism (SSCP) analysis, the mutation at exon 17 observed in the familial GIST was detectable by the use of direct sequencing but not by our SSCP method. In the present study, we examined the mutations at exon 17 and exon 13 by using direct sequencing. METHODS: Genomic DNA was extracted from formalin-fixed, paraffin-embedded GIST tissues. We could obtain 143 sporadic GIST cases appropriate for DNA analysis at exon 17 and 141 at exon 13. Exons 17 and 13 were amplified by using polymerase chain reaction and direct sequencing was conducted. RESULTS: No mutation was found at exon 17, and only one case with the mutation at exon 13 was observed. The GIST with the mutation at exon 13 was large and showed frequent mitosis, and the patient died of the recurrent GIST 3 years after the first operation. CONCLUSION: The mutation at exons 17 or 13 was considered to be very rare in sporadic GIST.

Aged↗

PubMed2003

Expression of the TSLC1 adhesion molecule in pulmonary epithelium and its down-regulation in pulmonary adenocarcinoma other than bronchioloalveolar carcinoma.

TSLC1 (tumor suppressor in lung cancer-1) is an adhesion molecule of the Ig superfamily that binds homophilically and mediates cell-cell interactions. Originally, TSLC1 was cloned as a candidate tumor suppressor from the genomic region that frequently exhibits loss of heterogeneity in human non-small-cell lung cancer (NSCLC). However, there have been no studies on TSLC1 expression in normal lungs or NSCLC. Here we show that pulmonary epithelial cells express TSLC1 and its expression levels are often decreased or lost in primary pulmonary adenocarcinoma, a major histologic type of NSCLC. Immunohistochemistry revealed that TSLC1 was localized at cell-cell boundaries of all columnar epithelial cells in mouse embryonic lungs of 10.5 and 13 days postcoitus. Similar staining patterns were observed in bronchiolar and alveolar epithelial cells of adult human lungs, suggesting a physiologic role for TSLC1 in interactions of these cells. Next we performed Western blot analyses of TSLC1 in 47 primary pulmonary adenocarcinomas and judged each tumor as either decreased or nondecreased by comparing TSLC1 expression levels of the tumor with the levels of normal lungs. The expression profiles had a significant relation to histologic subtypes but not to other clinicopathologic parameters. Sixteen bronchioloalveolar carcinomas (BACs) were all judged nondecreased, while 19 of 31 (63%) adenocarcinomas other than BAC were judged decreased (p < 0.0001). Immunohistochemistry of tumors judged nondecreased revealed that not only BAC cells but also tumor cells in lepidic growth components of adenocarcinomas other than BAC expressed TSLC1 on their lateral plasma membranes. These tumor cells are considered less invasive because they proliferate in a lepidic growth pattern along alveolar walls. Thus, the present results not only support the hypothesis that TSLC1 is a tumor suppressor of NSCLC but also suggest that preserved integrity of TSLC1 may contribute to less invasive phenotypes of lepidic growth tumor cells.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2003

Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c-kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain-of-function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germline mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR-ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule-based diagnosis and treatment of solid tumors.

Antineoplastic Agents↗

PubMed2002

SgIGSF: a new mast-cell adhesion molecule used for attachment to fibroblasts and transcriptionally regulated by MITF.

Microphthalmia transcription factor (MITF) is a basic-helix-loop-helix-leucine zipper-type transcription factor. The mutant mi and Mi(wh) alleles encode MITFs with deletion and alteration of a single amino acid, respectively, whereas the tg is a null mutation. In coculture with NIH/3T3 fibroblasts, the numbers of cultured mast cells (CMCs) derived from C57BL/6 (B6)(mi/mi), B6(Miwh/Miwh), and B6(tg/tg) mice that adhered to NIH/3T3 fibroblasts were one third as large as the number of B6(+/+) CMCs that adhered to NIH/3T3 fibroblasts. From a cDNA library of B6(+/+) CMCs, we subtracted messenger RNAs expressed by B6(mi/mi) CMCs and found a clone encoding SgIGSF, a recently identified member of the immunoglobulin superfamily. Northern and Western blot analyses revealed that SgIGSF was expressed in B6(+/+) CMCs but not in CMCs derived from MITF mutants. Immunocytochemical analysis showed that SgIGSF localized to the cell-to-cell contact areas between B6(+/+) CMCs and NIH/3T3 fibroblasts. Transfection of B6(mi/mi) and B6(tg/tg) CMCs with SgIGSF cDNA normalized their adhesion to NIH/3T3 fibroblasts. NIH/3T3 fibroblasts did not express SgIGSF, indicating that SgIGSF acts as a heterophilic adhesion molecule. Transfection of B6(tg/tg) CMCs with normal MITF cDNA elevated their SgIGSF expression to normal levels. These results indicated that SgIGSF mediated the adhesion of CMCs to fibroblasts and that the transcription of SgIGSF was critically regulated by MITF.

3T3 Cells↗

PubMed2002

Additive roles of XPA and MSH2 genes in UVB-induced skin tumorigenesis in mice.

We have made xeroderma pigmentosum group A gene (XPA)-knockout mice (XPA(-/-) mice). The XPA(-/-) mice had no detectable activity for nucleotide excision repair (NER) and showed a high incidence of UVB-induced skin tumorigenesis. We have also found that cell lines derived from skin cancers in UVB-irradiated XPA(-/-) mice become tolerant to UV-irradiation and showed abnormal UV-induced cell cycle checkpoints and decreased mismatch repair (MMR) activity. These results suggested that the MMR-downregulation may help cells escape killing by UV-irradiation and thus MMR-deficient clones are selected for during the tumorigenic transformation of XPA(-/-) cells. In this report, we examined whether the incidence of UVB-induced skin tumorigenesis is enhanced in XPA(-/-)MSH2(-/-), XPA(-/-) and MSH2(-/-) mice when compared with that in wild-type mice. Our results indicate that the MSH2-deficiency caused a high incidence of spontaneous and UVB-induced skin tumorigenesis and the XPA and MSH2 genes have additive roles in the UV-induced skin tumorigenesis.

Animals↗

PubMed2002

Additive effect of mouse genetic background and mutation of MITF gene on decrease of skin mast cells.

The mi transcription factor (MITF) is a basic-helix-loop-helix leucine zipper transcription factor and is encoded by mi locus. The mi/mi mutant mice showed a significant decrease of skin mast cells in C57BL/6 (B6) genetic background but not in WB genetic background. Kit ligand (KitL) is the most important growth factor for development of mast cells, and the decrease of skin mast cells in B6-mi/mi mice was attributable to the reduced expression of c-kit receptor tyrosine kinase (KIT) that is a receptor for KitL. However, the expression level of KIT in WB-mi/mi mast cells was comparable with that of B6-mi/mi mast cells, suggesting that a factor compensating the reduced expression of KIT was present in WB-mi/mi mice. By linkage analysis, such a factor was mapped on chromosome 10. The mapped position was closely located to the KitL locus. Two alternative spliced forms are known in KitL mRNA: KL-1 and KL-2. Soluble KitL, which is important for development of skin mast cells, is produced more efficiently from KL-1 mRNA than from KL-2 mRNA. The KL-1/KL-2 ratio was higher in WB-mi/mi than in B6-mi/mi mice, suggesting that the larger amount of soluble KitL may compensate for the reduced expression of KIT in WB-mi/mi mice.

Alternative Splicing↗

PubMed2002

A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis.

We generated a mouse line in which the src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130(F759/F759)). The gp130(F759/F759) mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130(F759/F759) T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

Amino Acid Substitution↗