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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A critical issue in understanding receptor tyrosine kinase signaling is the individual contribution of diverse signaling pathways in regulating cellular growth, survival, and migration. We generated a functionally and biochemically inert c-Kit receptor that lacked the binding sites for seven early signaling pathways. Restoring the Src family kinase (SFK) binding sites in the mutated c-Kit receptor restored cellular survival and migration but only partially rescued proliferation and was associated with the rescue of the Ras/mitogen-activated protein kinase, Rac/JNK kinase, and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt pathways. In contrast, restoring the PI-3 kinase binding site in the mutated receptor did not affect cellular proliferation but resulted in a modest correction in cell survival and migration, despite a complete rescue in the activation of the PI-3 kinase/Akt pathway. Surprisingly, restoring the binding sites for Grb2, Grb7, or phospholipase C-gamma had no effect on cellular growth or survival, migration, or activation of any of the downstream signaling pathways. These results argue that SFKs play a unique role in the control of multiple cellular functions and in the activation of distinct biochemical pathways via c-Kit.
Mol Cell Biol 2004 Feb
PMID:c-Kit-mediated overlapping and unique functional and biochemical outcomes via diverse signaling pathways. 1472 82

Bispecific antibodies (BiAbs) are being used to target T cells or other immune cells to antigen-specific tumor targets. Anti-CD3 activated T cells (ATC) armed with anti-CD3 x anti-HER2 BiAb (HER2Bi) have been used to target Her2/neu + breast and prostate carcinoma cells. We adapted BiAb technology to target stem cells to injured myocardium. Since myocardial infarctions can lead to cardiac death and disability, rapid repair and rejuvenation of damaged myocardium is critically needed. Effective homing of stem cells and transdifferentiation of the stem cells into functional elements of the myocardium is needed for repair of damaged myocardium. We use a BiAb that binds c-kit on murine stem cells and VCAM-1 adhesion molecules up-regulated on injured myocardial cells. To test for specific binding and homing in a mouse, we produced anti-c-kit x anti-VCAM-1 to target purified Lin-Sca+ murine stem cells to the injured myocardium. Mice with infarcts created by ligation of the left anterior descending artery (LAD) were directly injected with armed stem cells or injected via the internal jugular vein (IJ) with FACS sorted Lin-Sca+ stem cells from bone marrow after fluorescent dye labeling. There were increased numbers of armed Lin-Sca+ cells retained in infracted myocardium after direct injection of armed Lin-Sca+ cells and increased numbers of Lin-Sca+ cells that were found in injured myocardium after IJ injection. These results suggest that stem cells retargeted with BiAb can be directly injected and retained by injured myocardium or targeted to injured myocardial tissues for tissue regeneration.
Blood Cells Mol Dis
PMID:Targeting of Lin-Sca+ hematopoietic stem cells with bispecific antibodies to injured myocardium. 1475 18

Activated mast cells release stored and newly synthesized mediators that influence the caliber and responsiveness of inflamed airways. In this work, we show that alloimmune-mediated mechanisms induce mast cell activation and expression of CC chemokines in remodeling rat tracheal allografts. Decreased expression of rat mast cell protease (RMCP) I and II, in concert with tryptase release in tracheal allografts, identified degranulation of stored serine proteases as an early mast cell response to allotransplantation. Transient upregulation of c-Kit expression occurred in a synchronous manner, suggesting that c-Kit receptor signaling controls mast cell responses. Increased expression of CC chemokine ligand (CCL) 2 and CCL3 by RMCP I-positive cells identified mast cells as epithelial and mesenchymal sources of chemoattractant chemokines in allograft airways. Cyclosporin A immunosuppression both attenuated and delayed these changes in mast cell phenotypes. Incubation of rat basophil leukemia 2H3 cells with CCL2 or CCL3 decreased surface c-Kit expression, an effect blocked by protease inhibitors. By controlling surface receptor availability, CC chemokines may regulate c-Kit signaling via a novel proteolytic mechanism. These data suggest that targeting alloimmune responses and restoring quiescence of mast cells may attenuate the development of fibroproliferative and obstructive distortions of bronchiolar architecture in lung allografts.
Am J Respir Cell Mol Biol 2004 Aug
PMID:Induction of mast cell activation and CC chemokine responses in remodeling tracheal allografts. 1505 85

Ovulated eggs during a female's reproductive life are derived from a pool of primordial follicles arrested in prophase of the first meiotic division. When follicles leave the resting pool they undergo a primordial to primary follicle transition and will grow and develop until either ovulation occurs or follicles undergo atresia. Several growth factors have been implicated as acting locally within the ovary to regulate the primordial to primary follicle transition. How these growth factors may interact and cooperate to perform this vital function remains to be elucidated. The objective of the current study is to investigate interactions between kit ligand (KL) (i.e. stem cell factor) and basic fibroblast growth factor (bFGF) that promote the primordial to primary follicle transition in rat ovaries. Ovaries were removed from 4-day-old rat pups and cultured for 2 weeks with KL alone or with KL and a neutralizing antibody against bFGF. The ability of KL treatment to increase primordial follicle transition was blocked with a bFGF neutralizing antibody. In addition, ovary cultures were treated with bFGF alone or with bFGF and an anti-c-kit receptor antibody which blocks KL signaling. The ability of bFGF treatment to increase primordial follicle transition was blocked with an anti-c-kit receptor antibody. Observations indicate that both KL and bFGF must be active in order to optimally promote the changes that occur in oocytes, granulosa cells, and stromal/interstitial cells when primordial follicles initiate development. Cultured ovaries were treated with either KL or bFGF for 3 days and then bFGF and KL mRNA expression levels in the whole ovary were measured. KL was not found to regulate bFGF expression. In contrast, bFGF treatment was found to increase KL mRNA expression in cultured ovaries. These observations suggest that one function of the oocyte-derived bFGF is to increase the granulosa derived KL expression and that both KL and bFGF are required to optimally promote primordial to primary follicle transition. Elucidating the cell-cell interactions that mediate this network of specific locally derived growth factors is critical to understanding the physiology of the primordial to primary follicle transition.
Mol Cell Endocrinol 2004 Feb 12
PMID:Kit ligand and basic fibroblast growth factor interactions in the induction of ovarian primordial to primary follicle transition. 1506 41

The existence of a complex population of mRNA in human sperm is well documented but their role is not yet elucidated. Using discontinuous density gradients, we have isolated high and low motile sperm from the same semen sample. The levels of different transcripts coding for molecules either involved in nuclear condensation (protamines 1 and 2) or in capacitation [endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS) and c-myc] were then assessed in the two populations using semi-quantitative RT-PCR. Sperm viability was estimated by eosin-nigrosin staining and by hypo-osmotic swelling test; apoptosis percentage was measured by the TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling technique. The contamination by somatic and germ cells was assessed by looking for specific molecular markers of these cells, respectively CD-45 and E-cadherin for somatic cells and c-kit for germ cells. The viability of sperm was unchanged in high and low motile fractions, as well as DNA fragmentation percentage. The amount of Prm-1 mRNA was significantly higher in low density motile than in the high motile fraction. In most of high motile sperm samples eNOS and nNOS transcripts were undetectable whereas they were present in the low motile sperm. In contrast, no significant variation was found in the c-myc/Prm-2 mRNA ratio between the two populations. Moreover, a partial or complete disappearance of c-myc transcripts was observed after capacitation. Thus analysing mRNA profiles could be helpful as a diagnostic tool and prognosis value for fertilization.
Mol Hum Reprod 2004 Jul
PMID:Analysis and significance of mRNA in human ejaculated sperm from normozoospermic donors: relationship to sperm motility and capacitation. 1510 Mar 85

Differentiation of B lymphocytes can be efficiently obtained when multipotent hematopoietic precursors are cocultured with stromal cell lines and soluble growth factors. Stromal cell lines provide yet-undefined signals required for the expansion of the precursor population and/or lineage commitment and soluble mediators. In consequence, the type of the exogenously added interleukins depends on the stromal support used in the assay. In contrast to S17 and OP9 stroma, the fibroblast line NIH3T3 does not support B-cell precursor expansion of CD19(+) fetal liver cells; neither does it induce B-lineage differentiation from embryonic multipotent progenitors, in the absence of added cytokines. Under these conditions c-kit ligand, interleukin-7 (IL-7), and Flt3 ligand (Flt3-L) are added to the cultures to ensure optimal B-cell differentiation. Another cytokine, stroma-derived lymphopoietin, can also be used instead of IL-7 in embryonic but not adult hematopoietic precursors.
Methods Mol Biol 2004
PMID:Differentiation of B lymphocytes from hematopoietic stem cells. 1514 13

Inflammatory fibroid polyp (IFP) of the gastrointestinal tract is an uncommon proliferative lesion. When sampled by biopsy, IFP can be mistaken for various lesions, from granulation tissue to high-grade sarcoma. We present an unusual case of IFP and review a large series of IFPs to characterize clinical, histologic, and molecular features of diagnostic value. A total of 42 IFPs were gathered from the pathology archives of the University of Pittsburgh Medical Center over the past 22 years. Clinical, histopathologic, and immunohistochemical features were collected. A random subset of IFPs (n = 12) underwent microdissection genotyping for a broad panel of tumor suppressor gene-associated mutations (loss of heterozygosity). IFPs occurred in both sexes (male, 17; female, 25) over a broad age range (29-85 years). IFPs varied in size from 0.2 to 8 cm. The stomach (n = 19) was the most common location, followed by large bowel (n = 13) and small bowel (n = 10). Most IFPs displayed typical morphologic features (eosinophils admixed with loose, mature fibrous tissue), and in 2 instances, sampled by biopsy, IFP was confused for sarcoma. All IFPs lacked c-kit staining. No mutations were identified in any IFPs examined. IFP is a clinically underrecognized entity with unique morphologic and immunohistochemical features. On biopsy alone, the differential diagnosis may include sarcoma and other malignancies. The absence of mutational change may help to exclude malignant lesions.
Appl Immunohistochem Mol Morphol 2004 Mar
PMID:Inflammatory fibroid polyps of the gastrointestinal tract: clinical, pathologic, and molecular characteristics. 1516 21

Myotonic dystrophy 1 (DM1) is a multi-system disorder characterized by endocrine defects that include testicular and tubular atrophy, oligospermia, Leydig cell hyperproliferation and increased follicle stimulating hormone (FSH) levels. DM1 results from a CTG expansion that causes transcriptional silencing of the flanking SIX5 allele. Loss of Six5 results in male sterility and a progressive decrease in testicular mass with age. We demonstrate a strict requirement of Six5 for both spermatogenic cell survival and spermiogenesis. Leydig cell hyperproliferation and increased intra-testicular testosterone levels are observed in the Six5-/- mice. Although increased FSH levels are observed in the Six5+/- and Six5-/- mice, serum testosterone levels and intra-testicular inhibin alpha and inhibin beta B levels are not altered in the Six5 mutant animals when compared with controls. Significantly, steady-state c-Kit levels are reduced in the Six5-/- testis. Thus, decreased c-Kit levels could contribute to the elevated spermatogenic cell apoptosis and Leydig cell hyperproliferation in the Six5-/- mice. The results support the hypothesis that the reduced SIX5 levels contribute to the male reproductive defects in DM1.
Hum Mol Genet 2004 Jul 15
PMID:Six5 is required for spermatogenic cell survival and spermiogenesis. 1516 33

Bcr-Abl kinase is known to reverse apoptosis of cytokine-dependent cells due to cytokine deprivation, although it has been controversial whether chronic myeloid leukemia (CML) progenitors have the potential to survive under conditions in which there are limited amounts of cytokines. Here we demonstrate that early hematopoietic progenitors (Sca-1(+) c-Kit(+) Lin(-)) isolated from normal mice rapidly undergo apoptosis in the absence of cytokines. In these cells, the expression of Bim, a proapoptotic relative of Bcl-2 which plays a key role in the cytokine-mediated survival system, is induced. In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate. In addition, the expression levels of Bim are uniformly low in cell lines established from patients in the blast crisis phase of CML, and imatinib induced Bim in these cells. Moreover, small interfering RNA that reduces the expression level of Bim effectively rescues CML cells from apoptosis caused by imatinib. These findings suggest that Bim plays an important role in the apoptosis of early hematopoietic progenitors and that Bcr-Abl supports cell survival in part through downregulation of this cell death activator.
Mol Cell Biol 2004 Jul
PMID:Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors. 1522 21

Members of the homeobox family of transcription factors are major regulators of hematopoiesis. Overexpression of either HOXB4 or HOXA9 in primitive marrow cells enhances the expansion of hematopoietic stem cells (HSCs). However, little is known of how expression or function of these proteins is regulated during hematopoiesis under physiological conditions. In our previous studies we demonstrated that thrombopoietin (TPO) enhances levels of HOXB4 mRNA in primitive hematopoietic cells (K. Kirito, N. Fox, and K. Kaushansky, Blood 102:3172-3178, 2003). To extend our studies, we investigated the effects of TPO on HOXA9 in this same cell population. Although overall levels of the transcription factor were not affected, we found that TPO induced the nuclear import of HOXA9 both in UT-7/TPO cells and in primitive Sca-1(+)/c-kit(+)/Gr-1(-) hematopoietic cells in a mitogen-activated protein kinase-dependent fashion. TPO also controlled MEIS1 expression at mRNA levels, at least in part due to phosphatidylinositol 3-kinase activation. Collectively, TPO modulates the function of HOXA9 by leading to its nuclear translocation, likely mediated by effects on its partner protein MEIS1, and potentially due to two newly identified nuclear localization signals. Our data suggest that TPO controls HSC development through the regulation of multiple members of the Hox family of transcription factors through multiple mechanisms.
Mol Cell Biol 2004 Aug
PMID:Thrombopoietin induces HOXA9 nuclear transport in immature hematopoietic cells: potential mechanism by which the hormone favorably affects hematopoietic stem cells. 1525 42


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