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

The endometrial stroma plays a decisive role in sustaining the gland epithelium along the menstrual cycle, and in preparing the microenvironment that allows embryo implantation. The stroma undergoes important changes during the menstrual cycle that affects both the cell number and differentiation. These changes are regulated by both estrogen and progesterone. Stromal sarcomas are extremely rare, occurring much less than any other uterine tumor. Their origin and biology are poorly understood. The purpose of this work was to try to learn more about the stromal physiology, and also to ascertain whether the stromal sarcoma has characteristics of hormone dependence. We studied the presence of estrogen receptors (ER), progesterone receptors (PR) and the stress-responsive protein of 27K (srp27, a protein first described as an estrogen-induced 24K protein in MCF-7 cells) in both normal stroma and stromal sarcoma. The ER and PR were measured by exchange assays. The srp 27 was studied both by Western-blot and by IHC by means of specific monoclonal antibodies. The stromal sarcomas studied showed a high concentration of both ER (96 to 116 fmol/mg prot.) and PR (565 to 995 fmol/mg prot.). These amounts of ER and PR were higher than the mean found in normal endometrium during the proliferative phase (43 and 637 fmol/mg prot., respectively), and much higher than that of the secretory phase (17 and 229 fmol/mg prot., respectively). The srp27 characterized by Western-blot in both the normal stroma and stromal sarcoma was found to be similar to the srp27 of breast cancer. The IHC results showed a very low expression of srp27 in the stroma during the proliferative phase that increases when the endometrium enters the secretory phase. The low-malignancy grade stromal sarcomas showed abundant expression of srp27, but the high-malignancy grade sarcomas showed no expression of srp27. The obtained results prove the stroma capability to express the srp27. A negative correlation between malignancy of stromal tumors and srp27 expression was found. The presence of ER and PR in some stromal sarcomas proves that they have characteristics of hormone responsiveness. These findings suggest that ER and PR assays should be routinely performed in stromal sarcomas as well as in endometrial adenocarcinomas, and also that antiestrogenic drugs might be considered for the treatment of ER and PR positive stromal sarcomas.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Endometrial stromal sarcoma expression of estrogen receptors, progesterone receptors and estrogen-induced srp27 (24K) suggests hormone responsiveness. 156 30

Inhibin-alpha-deficient mutant mice have been generated by a targeted deletion of the inhibin-alpha gene through homologous recombination in murine embryonic stem cells. Essentially all of the homozygous mutants develop gonadal sex cord-stromal tumors. To investigate their endocrine and proliferative characteristics, gonadal tumor cells were maintained in vitro. Cells from inhibin-alpha-deficient mice multiplied poorly; however, cells from mice deficient in both inhibin-alpha and p53 proliferated rapidly and showed higher saturation density and plating efficiency, thus allowing the establishment of clonal tumor cell lines. Although negligible estrogen and testosterone was produced by the clonal cells, high levels of progesterone were secreted. A clonal testis tumor cell line (inhibin-alpha/p53 deficient) showed no response to exogenous FSH, human CG (hCG), or inhibin A but exhibited a 6- to 8-fold increase in progesterone production in response to forskolin treatment. The stimulatory effect of forskolin was, however, partially blocked by activin treatment. Northern blot analysis revealed inhibin beta A and beta B mRNA expression in these cells. Furthermore, Western blot analyses indicated the secretion of the beta A-subunit protein. We further tested the role of activin on tumor cell growth. Treatment with follistatin, an activin-binding protein, inhibited tumor cell replication in a dose-dependent manner. In contrast, treatment with activin A stimulated tumor cell growth by itself and partially blocked follistatin action. Incorporation of thymidine into DNA of these cells was also stimulated by activin. In addition, treatment with antiactivin A serum inhibited tumor cell replication and blocked the stimulatory action of activin on cell growth. The activin action is likely mediated by specific receptors because cross-linking of [125]activin to the 50-55 kilodalton type I and 75-80 kilodalton type II receptors was found using sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. Northern blot analysis also revealed follistatin mRNA expression in the tumor cells, suggesting these cells are related to granulosa cells. Our findings indicate that activin can act as an autocrine growth factor in stimulating the proliferation of gonadal tumor cell lines derived from inhibin-alpha and p53-deficient mice and inhibits progesterone production. These tumor cell lines are useful for studies on the regulation of gonadal cell proliferation and steroidogenesis as well as the signaling pathway mediating activin action.
Mol Endocrinol 1994 Aug
PMID:Characterization of gonadal sex cord-stromal tumor cell lines from inhibin-alpha and p53-deficient mice: the role of activin as an autocrine growth factor. 799 39

Trisomy of chromosome 12 has been frequently described in various neoplasms, particularly in tumors of the female genitourinary tract. Fluorescence in situ hybridization with a centromeric repetitive DNA probe, specific for chromosome 12, was done to detect such cytogenic changes on frozen-tissue sections from 10 cases of ovarian sex cord stromal tumors. The case series was composed by granulosa cell tumors (four cases), fibromas (four cases), thecoma (one case), and Sertoli-Leydig cell tumor (one case). In granulosa cell tumors, the range of trisomy was 12 to 32% and in fibromas 8 to 22%, whereas in the single case of thecoma trisomy was present in 8% and in the Sertoli-Leydig cell tumor in 4% of the nuclei examined. These results represent an additional series of cases of trisomy 12 in ovarian neoplasms, namely, in ovarian sex cord stromal tumors.
Diagn Mol Pathol 1993 Jun
PMID:Detection of trisomy 12 on ovarian sex cord stromal tumors by fluorescence in situ hybridization. 826 83

Activins and inhibins, members of the transforming growth factor-beta superfamily, are involved in diverse physiological and developmental processes. We have previously shown that mice deficient in alpha-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parietal cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibin-deficient mice secrete high levels of activins. In addition, Northern blot analysis has localized activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced activins act through ActRII to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of activin signaling through ActRII in vivo, we generated compound homozygous mutant mice deficient in both alpha-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of activin signaling through ActRII in hepatocytes and the glandular stomach causes the hepatocellular necrosis and depletion of parietal cells in the glandular stomach as well as the severe weight loss in vivo.
Mol Endocrinol 1996 May
PMID:Activin signaling through activin receptor type II causes the cachexia-like symptoms in inhibin-deficient mice. 873 84

Activins are TGFbeta family members known to mediate a variety of developmental events. We examined the effects of activins on the self-renewing epithelial lineages present in gastric units of the adult mouse stomach. These lineages are descended from multipotent stem cells located in the midportion of each unit. The stem cell and its immediate descendants can be identified by their morphological features. Studies of knockout mice lacking activins A or B, and/or activin type II receptors (ActRII) revealed that ActRII-mediated signaling is not required for normal gastric epithelial morphogenesis or homeostasis. Mice homozygous for a null allele of the alpha-inhibin gene (inha[m1/m1]) develop gonadal sex cord stromal tumors that secrete large amounts of activins A and B. Analysis of inha(m1/m1) mice, with or without gonads, established that supraphysiological levels of activins block differentiation of preparietal to acid-producing parietal cells, differentiation of neck cells to pepsinogen-producing zymogenic cells, and terminal differentiation of mucus-producing pit cells. ActRII mRNA is normally present in pit, parietal, and zymogenic cells. inha(m1/m1)actRII(m1/m1) compound homozygotes develop activin-secreting gonadal tumors but have no abnormalities in their gastric epithelium, indicating that persistent stimulation of ActRII-dependent signaling pathways produces pleiotrophic effects on gastric epithelial differentiation. When a lineage-specific promoter is used to ablate mature parietal cells with an attenuated diphtheria toxin A fragment in transgenic mice, there is increased proliferation of the multipotent gastric stem cell and its committed daughters and subsequent development of gastric neoplasia. Parietal cell loss in inha(m1/m1) mice is not associated with this proliferative response. These different responses to parietal cell loss suggest that stimulation of ActRII-dependent signaling pathways in inha(m1/m1) animals affects the proliferative activity of the stem cell and its immediate descendents. This finding may have therapeutic significance.
Mol Endocrinol 1998 Feb
PMID:Stimulation of activin receptor II signaling pathways inhibits differentiation of multiple gastric epithelial lineages. 948 61

The histogenesis of inflammatory fibroid polyps (IFP) of the gastrointestinal tract, focused on the cell of origin of the stromal cells, is a controversial subject. The reported CD34 reactivity in gastric IFP has implied a histogenetic relationship with a variety of CD34-reactive tumors, including gastrointestinal stromal tumors (GIST). In addition to bcl-2, the majority of GIST has expressed Kit, suggesting an origin in interstitial cells of Cajal (ICC), which are selectively localized around nerve plexuses. Gastric (12) and colonic (two) IFP from 13 patients were studied, using antibodies against CD34, bcl-2, and Kit. IFP expanded muscularis mucosae with prominent vascular channels, inflammatory infiltrates, proliferating stromal cells, and extracellular matrix material. Eleven gastric IFP exhibited concentric stromal proliferations (CP), particularly, around vessels, glands, and muscle bundles. Their stromal cells were CD34 reactive, bcl-2 nonreactive, and Kit nonreactive and showed fibroblast-like appearances with thin, long cytoplasmic processes. In contrast, one gastric and two colonic IFP showed no CP, and their stromal cells were CD34 nonreactive, bcl-2 nonreactive, and Kit nonreactive. IFP with CP may have a different histogenesis from IFP without CP. IFP with CP may originate from a subpopulation of dendritic interstitial cells other than ICC, predominantly localized around blood vessels and muscle fibers in muscularis mucosae of the stomach.
Appl Immunohistochem Mol Morphol 2000 Jun
PMID:Expression of CD34, bcl-2, and kit in inflammatory fibroid polyps of the gastrointestinal tract. 1093 62

Recently some reports have suggested that gastrointestinal stromal tumors (GIST) might originate from the interstitial cells of Cajal or differentiate into them because they express c-kit and/or CD34 and indicated that the majority of previously diagnosed smooth muscle tumors (SMT) actually belong to GIST, but are not true SMT. We, therefore, detected c-kit, CD34, SMA, and S-100 in 106 Chinese cases of gastrointestinal tumors, which were histopathologically diagnosed as smooth muscle tumors originally, to demonstrate the immunophenotypes of these tumors. The results showed that 73 cases had immunoreaction with c-kit and/or CD34, of which 48 cases showed coexpression with either SMA or S-100 or with both. A correlation between the immunophenotypes and known histopathological parameters was also shown here based on follow-up data. We suggest that the concept of GIST should not be used as an umbrella to cover all gastrointestinal mesenchymal tumors, but be defined in a narrow term as differing from true smooth muscle tumors.
Exp Mol Pathol 2002 Apr
PMID:Gastrointestinal stromal tumors: are they of cajal cell origin? 1189 Jul 26

Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the digestive tract. These tumors express the c-kit receptor tyrosine kinase, and many have activating mutations in the juxtamembrane region coded by the exon 11 of KIT. Detection of these mutations has prognostic and therapeutic impact. The aim of the study was to compare a new detection method by length analysis of polymerase chain reaction products (LAPP) to direct sequencing. The detection of either deletion or insertion mutations within the exon 11 of KIT was performed on genomic DNA extracted from 40 paraffin-embedded samples from 38 patients. Double-strand direct sequencing revealed a mutation in 25 of 40 samples. In two additional samples, a mutation was suspected but could not be determined by sequencing. LAPP revealed a mutation in 27 samples, corresponding to the 25 determined and 2 suspected samples. One of these latter samples contained three different alleles. Mutations corresponded to either deletions (n = 24) or insertion (n = 1) and had the same size with sequencing and LAPP. Our results show that LAPP is as accurate and more sensitive than direct sequencing for the detection of deletion or insertion mutations of exon 11 of KIT in gastrointestinal stromal tumors.
Diagn Mol Pathol 2002 Jun
PMID:Length analysis of polymerase chain reaction products: a sensitive and reliable technique for the detection of mutations in KIT exon 11 in gastrointestinal stromal tumors. 1204 14

Sex cord-stromal tumors represent approximately 4% of all testicular neoplasms. Leydig cell tumor (LCT) is the most common entity, followed by Sertoli cell tumor (SCT). Leydig cell tumor histologic diagnosis is usually easy, but occasional forms of LCT could mimic others neoplasms, especially SCT or variants of yolk sac tumor. The aim of this study was to investigate calretinin expression in LCT and SCT of the testis. We evaluated calretinin reactivity in formalin-fixed, paraffin-embedded sections of 10 LCT, three SCT, five Leydig cell hyperplasia, two Sertoli cell adenomas, eight seminomatous tumors, five nonseminomatous germ cell tumors (mixed tumor), one adenomatoid tumor, and two normal testes using a standard immunohistochemical technique with a microwave-mediated epitope retrieval. All cases of LCT showed a positive staining that was diffuse and intense, constantly cytoplasmic, and sometimes nuclear. A positive strong and diffuse cytoplasmic and sometimes nuclear staining was also observed in Leydig cell hyperplasia and in normal Leydig cells. No staining was seen in two of three cases of SCT, and focal staining was observed in the third case. Only rare scattered cells were weakly immunostained in the Sertoli cell nodules. Seminomatous and nonseminomatous germ cell tumors were negative. Calretinin is an interesting marker of normal and neoplastic Leydig cells of the testis and may be of value in the diagnosis of atypical LCT.
Appl Immunohistochem Mol Morphol 2002 Jun
PMID:Calretinin: a valuable marker of normal and neoplastic Leydig cells of the testis. 1205 35

Imatinib (Glivec; STI571) is an ATP-competitive kinase inhibitor of c-Abl, BCR/ABL, c-Kit, and platelet-derived growth factor receptor. Overexpression or constitutive activation of Kit by mutations have been associated with various malignancies. Mutations in the intracellular juxtamembrane region of Kit (e.g., V560G) are common in gastrointestinal stromal tumors and have been linked to poor prognosis. Mutations in the kinase domain of Kit (e.g., D816V) have been detected in mastocytosis, acute myeloid leukemia, and germ-cell tumors. To determine the sensitivity of Kit mutants to Imatinib in the same cellular background, wild-type Kit (WTKit), V560GKit and D816VKit were expressed in FDC-P1 cells. Growth of FDC(WTKit) was inhibited by Imatinib with GI50 (a concentration of drug at which 50% inhibition of growth occurs) of 0.1-0.2 microM but FDC(V560GKit) were more sensitive to Imatinib with a GI50 of 0.01-0.025 microM and FDC(D816VKit) were resistant to Imatinib with a GI50 greater than 5 microM. The naturally occurring isoforms of c-Kit did not differ in their sensitivity to Imatinib. Immunoprecipitation and Western blot analysis indicated that 1 microM Imatinib reduced phosphorylation of WTKit and completely blocked phosphorylation of V560GKit but did not affect D816VKit phosphorylation. In signaling studies, addition of stem cell factor (SCF) induced phosphorylation of ERK and Akt by WTKit, and ERK, Akt and STAT3 by V560GKit, which were all blocked by Imatinib. Imatinib also blocked the constitutive activation of Akt and STAT3 by V560GKit but had no affect on the constitutive activation of ERK, Akt, and STAT3 by D816VKit. Overall, these findings demonstrate the increased susceptibility of the Kit juxtamembrane mutant, V560G, and the resistance of the kinase domain mutant, D816V, to Imatinib compared with WTKit.
Mol Cancer Ther 2002 Oct
PMID:Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. 2207 14


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