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  1. Article: Cholecystitis and cholelithiasis associated with an intramural fasciitis-like proliferation and osseous metaplasia.

    Rege, Tanya A / Vargas, Sara O

    Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society

    2011  Volume 14, Issue 1, Page(s) 80–83

    Abstract: Fasciitis-like proliferations are said to be uncommon in the viscera; a fasciitis-like pattern of gallbladder injury may not be rare, but to our knowledge it has not been explicitly reported as such in any age group. Osseous metaplasia, or heterotopic ... ...

    Abstract Fasciitis-like proliferations are said to be uncommon in the viscera; a fasciitis-like pattern of gallbladder injury may not be rare, but to our knowledge it has not been explicitly reported as such in any age group. Osseous metaplasia, or heterotopic bone, in the gallbladder is rare and has not to our knowledge been reported in a pediatric patient. We report a 7-year-old boy with sickle cell disease who presented with right upper quadrant abdominal pain. An ultrasonograph demonstrated a dilated common bile duct with sludge and stones. A cholecystectomy was performed. Grossly the gallbladder showed numerous pigmented choleliths, and histologically there was cholecystitis with a fasciitis-like fibrous proliferation containing scattered osteoclast-like giant cells and an area of osseous metaplasia. This report, describing a pattern that could be termed "cholecystitis ossificans," expands the histologic spectrum of chronic cholecystitis, a common disease with a poorly understood pathogenesis.
    MeSH term(s) Anemia, Sickle Cell/complications ; Cell Proliferation ; Child ; Cholecystectomy ; Cholecystitis/complications ; Cholecystitis/pathology ; Cholecystitis/surgery ; Cholelithiasis/complications ; Cholelithiasis/pathology ; Cholelithiasis/surgery ; Fasciitis/complications ; Fasciitis/pathology ; Fasciitis/surgery ; Gallbladder/pathology ; Gallbladder/surgery ; Humans ; Male ; Metaplasia/complications ; Metaplasia/surgery ; Ossification, Heterotopic/complications ; Ossification, Heterotopic/pathology
    Language English
    Publishing date 2011-01
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 1463498-3
    ISSN 1615-5742 ; 1093-5266
    ISSN (online) 1615-5742
    ISSN 1093-5266
    DOI 10.2350/09-12-0772-CR.1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Long fascicular tissue fragments in desmoid fibromatosis by fine needle aspiration: a new cytologic feature.

    Rege, Tanya A / Madan, Rachna / Qian, Xiaohua

    Diagnostic cytopathology

    2012  Volume 40, Issue 1, Page(s) 45–47

    MeSH term(s) Adult ; Biopsy, Fine-Needle ; Cytodiagnosis ; Female ; Fibromatosis, Abdominal/pathology ; Humans
    Language English
    Publishing date 2012-01
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 632710-2
    ISSN 1097-0339 ; 8755-1039
    ISSN (online) 1097-0339
    ISSN 8755-1039
    DOI 10.1002/dc.21610
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Adenocarcinoma complicating ulcerative colitis presenting as multiple pseudopolyp-like lesions.

    Hamilton, Matthew J / Rege, Tanya A / Odze, Robert D

    Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

    2012  Volume 10, Issue 6, Page(s) xxv

    MeSH term(s) Adenocarcinoma/complications ; Adenocarcinoma/diagnosis ; Adenocarcinoma/pathology ; Adenocarcinoma/surgery ; Adult ; Colitis, Ulcerative/diagnosis ; Colitis, Ulcerative/pathology ; Colitis, Ulcerative/surgery ; Colonic Neoplasms/complications ; Colonic Neoplasms/diagnosis ; Colonic Neoplasms/pathology ; Colonic Neoplasms/surgery ; Histocytochemistry ; Humans ; Male ; Microscopy
    Language English
    Publishing date 2012-06
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 2119789-1
    ISSN 1542-7714 ; 1542-3565
    ISSN (online) 1542-7714
    ISSN 1542-3565
    DOI 10.1016/j.cgh.2011.10.040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis.

    Rege, Tanya A / Hagood, James S

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2006  Volume 20, Issue 8, Page(s) 1045–1054

    Abstract: Thy-1 (CD90) is a 25-37 kDa glycosylphosphatidylinositol (GPI) -anchored glycoprotein expressed on many cell types, including T cells, thymocytes, neurons, endothelial cells, and fibroblasts. Activation of Thy-1 can promote T cell activation, and this ... ...

    Abstract Thy-1 (CD90) is a 25-37 kDa glycosylphosphatidylinositol (GPI) -anchored glycoprotein expressed on many cell types, including T cells, thymocytes, neurons, endothelial cells, and fibroblasts. Activation of Thy-1 can promote T cell activation, and this role of Thy-1 is reviewed elsewhere. Thy-1 also affects numerous nonimmunologic biological processes, including cellular adhesion, neurite outgrowth, tumor growth, migration, and cell death. In reviewing the nonimmunologic functions of Thy-1, we discuss the phenotype of the Thy-1 null mouse, signaling pathways modulated by Thy-1, the role of the GPI anchor in Thy-1 localization to lipid rafts and signaling, and regulation of Thy-1 expression. Thy-1 is an important regulator of cell-cell and cell-matrix interactions, with important roles in nerve regeneration, metastasis, inflammation, and fibrosis.
    MeSH term(s) Animals ; Apoptosis ; Axons/physiology ; Cell Adhesion ; Cell Communication ; Cell Movement ; Extracellular Matrix/metabolism ; Fibrosis ; Humans ; Mice ; Neoplastic Processes ; Nerve Regeneration ; Thy-1 Antigens/physiology ; Tumor Suppressor Proteins/physiology
    Chemical Substances Thy-1 Antigens ; Tumor Suppressor Proteins
    Language English
    Publishing date 2006-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.05-5460rev
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Thy-1, a versatile modulator of signaling affecting cellular adhesion, proliferation, survival, and cytokine/growth factor responses.

    Rege, Tanya A / Hagood, James S

    Biochimica et biophysica acta

    2006  Volume 1763, Issue 10, Page(s) 991–999

    Abstract: Thy-1 is a 25-37 kDa glycosylphosphatidylinositol (GPI)-anchored protein involved in T cell activation, neurite outgrowth, apoptosis, tumor suppression, wound healing, and fibrosis. To mediate these diverse effects, Thy-1 participates in multiple ... ...

    Abstract Thy-1 is a 25-37 kDa glycosylphosphatidylinositol (GPI)-anchored protein involved in T cell activation, neurite outgrowth, apoptosis, tumor suppression, wound healing, and fibrosis. To mediate these diverse effects, Thy-1 participates in multiple signaling cascades. In this review, we discuss Thy-1 signaling primarily in non-immunologic cell types, including neurons, mesangial cells, ovarian cancer cells, nasopharyngeal carcinoma cells, endothelial cells, and fibroblasts. We review the current literature regarding Thy-1 signaling via integrins, protein tyrosine kinases, and cytokines and growth factors; and the roles of these signaling pathways in cellular adhesion, apoptosis, cell proliferation, and cell adhesion and migration. We also discuss the role of Thy-1 localization to lipid rafts, and of the GPI anchor in Thy-1 signaling. Ongoing research on the mechanisms of Thy-1 signaling will add to our understanding of the diverse physiologic and pathologic processes in which Thy-1 plays a role.
    MeSH term(s) Animals ; Apoptosis ; Cell Adhesion ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Cytokines/metabolism ; Cytokines/physiology ; Integrins/metabolism ; Integrins/physiology ; Intercellular Signaling Peptides and Proteins/metabolism ; Intercellular Signaling Peptides and Proteins/physiology ; Membrane Microdomains/metabolism ; Mice ; Models, Biological ; Protein-Tyrosine Kinases/metabolism ; Protein-Tyrosine Kinases/physiology ; Signal Transduction ; Thy-1 Antigens/genetics ; Thy-1 Antigens/metabolism ; Thy-1 Antigens/physiology
    Chemical Substances Cytokines ; Integrins ; Intercellular Signaling Peptides and Proteins ; Thy-1 Antigens ; Protein-Tyrosine Kinases (EC 2.7.10.1)
    Language English
    Publishing date 2006-10
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbamcr.2006.08.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis

    Rege, Tanya A / Hagood, James S

    FASEB journal. 2006 June, v. 20, no. 8

    2006  

    Abstract: ... inflammation, and fibrosis.--Rege, T. A., Hagood, J. S. Thy-1 as a regulator of cell-cell and cell-matrix ...

    Abstract Thy-1 (CD90) is a 25-37 kDa glycosylphosphatidylinositol (GPI) -anchored glycoprotein expressed on many cell types, including T cells, thymocytes, neurons, endothelial cells, and fibroblasts. Activation of Thy-1 can promote T cell activation, and this role of Thy-1 is reviewed elsewhere. Thy-1 also affects numerous nonimmunologic biological processes, including cellular adhesion, neurite outgrowth, tumor growth, migration, and cell death. In reviewing the nonimmunologic functions of Thy-1, we discuss the phenotype of the Thy-1 null mouse, signaling pathways modulated by Thy-1, the role of the GPI anchor in Thy-1 localization to lipid rafts and signaling, and regulation of Thy-1 expression. Thy-1 is an important regulator of cell-cell and cell-matrix interactions, with important roles in nerve regeneration, metastasis, inflammation, and fibrosis.--Rege, T. A., Hagood, J. S. Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis.
    Language English
    Dates of publication 2006-06
    Size p. 1045-1054.
    Publishing place The Federation of American Societies for Experimental Biology
    Document type Article
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    Database NAL-Catalogue (AGRICOLA)

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  7. Article: Endogenous inhibitors of angiogenesis in malignant gliomas: nature's antiangiogenic therapy.

    Rege, Tanya A / Fears, Constance Y / Gladson, Candece L

    Neuro-oncology

    2005  Volume 7, Issue 2, Page(s) 106–121

    Abstract: Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm(3). This observation, along with the accessibility of tumor vessels to therapeutic targeting, has resulted in a research focus on inhibitors of angiogenesis. A number of ... ...

    Abstract Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm(3). This observation, along with the accessibility of tumor vessels to therapeutic targeting, has resulted in a research focus on inhibitors of angiogenesis. A number of endogenous inhibitors of angiogenesis are found in the body. Some of these are synthesized by specific cells in different organs, and others are created by extracellular proteolytic cleavage of plasma-derived or extracellular matrix-localized proteins. In this review, we focus on angiostatin, endostatin, PEX, pigment epithelial-derived factor, and thrombospondin (TSP)-1 and -2, either because these molecules are expressed in malignant glioma biopsies or because animal studies in malignant glioma models have suggested that their therapeutic administration could be efficacious. We review the known mechanisms of action, potential receptors, expression in glioma biopsy samples, and studies testing their potential therapeutic efficacy in animal models of malignant glioma. Two conclusions can be made regarding the mechanisms of action of these inhibitors: (1) Several of these inhibitors appear to mediate their antiangiogenic effect through multiple protein-protein interactions that inhibit the function of proangiogenic molecules rather than through a specific receptor-mediated signaling event, and (2) TSP-1 and TSP-2 appear to mediate their antiangiogenic effect, at least in part, through a specific receptor, CD36, which initiates the antiangiogenic signal. Although not proven in gliomas, evidence suggests that expression of specific endogenous inhibitors of angiogenesis in certain organs may be part of a host antitumor response. The studies reviewed here suggest that new antiangiogenic therapies for malignant gliomas offer exciting promise as nontoxic, growth-inhibitory agents.
    MeSH term(s) Angiogenesis Inhibitors/pharmacology ; Angiostatins/pharmacology ; Animals ; Brain Neoplasms/drug therapy ; Endostatins/chemistry ; Endostatins/pharmacology ; Eye Proteins/pharmacology ; Glioma/drug therapy ; Humans ; Neovascularization, Pathologic/drug therapy ; Nerve Growth Factors/pharmacology ; Peptide Fragments/pharmacology ; Serpins/pharmacology ; Signal Transduction/physiology ; Thrombospondin 1/chemistry ; Thrombospondin 1/pharmacology ; Thrombospondins/chemistry ; Thrombospondins/pharmacology
    Chemical Substances Angiogenesis Inhibitors ; Endostatins ; Eye Proteins ; Nerve Growth Factors ; Peptide Fragments ; Serpins ; Thrombospondin 1 ; Thrombospondins ; pigment epithelium-derived factor ; thrombospondin 2 ; Angiostatins (86090-08-6)
    Language English
    Publishing date 2005-04
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 2028601-6
    ISSN 1523-5866 ; 1522-8517
    ISSN (online) 1523-5866
    ISSN 1522-8517
    DOI 10.1215/S115285170400119X
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: "Pediatric-type" gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior.

    Rege, Tanya A / Wagner, Andrew J / Corless, Christopher L / Heinrich, Michael C / Hornick, Jason L

    The American journal of surgical pathology

    2011  Volume 35, Issue 4, Page(s) 495–504

    Abstract: Gastrointestinal stromal tumors (GISTs) rarely affect children, mainly girls. Pediatric GISTs typically arise in the stomach as multifocal tumors with a multinodular growth pattern, epithelioid morphology, lymph node metastases, an absence of KIT and ... ...

    Abstract Gastrointestinal stromal tumors (GISTs) rarely affect children, mainly girls. Pediatric GISTs typically arise in the stomach as multifocal tumors with a multinodular growth pattern, epithelioid morphology, lymph node metastases, an absence of KIT and PDGFRA gene mutations, and indolent behavior. Occasional GISTs in adults show similar features. Such tumors are not widely recognized. GISTs with a multinodular growth pattern in patients over the age of 18 years were retrieved from surgical and consultation files. Hematoxylin and eosin-stained slides were reviewed, immunohistochemistry was performed, and KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12, 14, and 18) genes were screened for mutations. Clinical follow-up was obtained. Sixteen cases were identified, affecting 13 women and 3 men (median age, 31.5 y; range, 19 to 56 y), all in the stomach. The mean tumor size was 5.4 cm (range, 1.8 to 11 cm); 4 were multifocal. All tumors showed a multinodular or plexiform architecture and epithelioid (N=3) or mixed epithelioid and spindle cell (N=13) morphology. Five tumors had vascular invasion; 6 had focal necrosis. Mitotic activity ranged from 3 to 156/50 high-power fields (8 tumors had ≤5/50 high-power fields). Using Armed Forces Institute of Pathology risk stratification, categories for primary tumors were: none (N=2), very low risk (N=3), low risk (N=3), moderate risk (N=3), and high risk (N=5). By immunohistochemistry, all tumors were positive for KIT, 82% DOG1, 72% CD34, 18% caldesmon, 9% S-100, 8% smooth muscle actin, and 0% desmin. All tumors were wild type for KIT and PDGFRA in the exons that were screened. At primary resection, 9 patients (56%) had lymph node metastases and 3 patients had liver metastases. Follow-up ranged from 16 months to 16 years (median, 5 y). Two tumors recurred locally in the stomach and 7 patients developed subsequent metastases to the lymph nodes (N=5), liver (N=3), and peritoneum/omentum (N=3). Primary tumors from 7 patients with metastases were Armed Forces Institute of Pathology low risk, very low risk, or no risk of recurrence. None of the metastatic tumors responded to treatment with imatinib mesylate. One patient died of disseminated liver and intra-abdominal metastases and the remaining patients were alive at last follow-up. Gastric GISTs in adults with a multinodular or plexiform growth pattern and epithelioid or mixed morphology are similar to pediatric GISTs. Unlike conventional adult GISTs, this distinctive subset predominantly affects women, often metastasizes to lymph nodes, and lacks mutations in KIT and PDGFRA. Current risk assessment criteria do not reliably predict behavior for this group. Although metastases are common and most tumors are imatinib resistant, they pursue a relatively indolent clinical course. Recognition of "pediatric-type" GISTs in adults is critical for prognosis, appropriate therapy, and follow-up.
    MeSH term(s) Adult ; Biomarkers, Tumor/metabolism ; Chemotherapy, Adjuvant ; DNA Mutational Analysis ; DNA, Neoplasm/genetics ; Female ; Gastrectomy ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/metabolism ; Gastrointestinal Stromal Tumors/secondary ; Genotype ; Humans ; Lymph Nodes/pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Prognosis ; Proto-Oncogene Proteins c-kit/genetics ; Proto-Oncogene Proteins c-kit/metabolism ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; Young Adult
    Chemical Substances Biomarkers, Tumor ; DNA, Neoplasm ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1)
    Language English
    Publishing date 2011-04
    Publishing country United States
    Document type Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 752964-8
    ISSN 1532-0979 ; 0147-5185
    ISSN (online) 1532-0979
    ISSN 0147-5185
    DOI 10.1097/PAS.0b013e31820e5f7d
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1.

    Rege, Tanya A / Stewart, Jerry / Dranka, Brian / Benveniste, Etty N / Silverstein, Roy L / Gladson, Candece L

    Journal of cellular physiology

    2008  Volume 218, Issue 1, Page(s) 94–103

    Abstract: Thrombospondin-1 (TSP-1) treatment of dermal microvascular endothelial cells (MvEC) has been shown to upregulate Fas ligand (FasL) and to induce apoptosis by a mechanism that requires caspase-8 activity. We have examined the potential anti-angiogenic ... ...

    Abstract Thrombospondin-1 (TSP-1) treatment of dermal microvascular endothelial cells (MvEC) has been shown to upregulate Fas ligand (FasL) and to induce apoptosis by a mechanism that requires caspase-8 activity. We have examined the potential anti-angiogenic effects of TSP-1 on primary human brain MvEC. The addition of TSP-1 to primary human brain MvEC cultured as monolayers on type 1 collagen, induced cell death and apoptosis (evidenced by caspase-3 cleavage) in a dose- (5-30 nM) and time-dependent (maximal at 17 h) manner. TSP-1 treatment for 17 h induced caspase-3 cleavage that required caspase-8 activity and the tumor necrosis factor receptor 1 (TNF-R1). We did not find a requirement for Fas, or the tumor necrosis-related apoptosis-inducing ligand receptors (TRAIL-R) 1 and 2. We confirmed the findings using caspase inhibitors, blocking antibodies and small interfering RNA (siRNA). Further analysis indicated that the TSP-1 induction of caspase-3 cleavage of primary human brain MvEC adherent to collagen required the synthesis of new message and protein, and that TSP-1 induced the expression of TNFalpha mRNA and protein. Consistent with these findings, when the primary human brain MvEC were propagated on collagen gels mAb anti-TNF-R1 reversed the inhibitory effect, in part, of TSP-1 on tube formation and branching. These data identify a novel mechanism whereby TSP-1 can inhibit angiogenesis-through induction of apoptosis in a process mediated by TNF-R1.
    MeSH term(s) Apoptosis/drug effects ; Base Sequence ; Brain/cytology ; Brain/metabolism ; CD36 Antigens/metabolism ; Caspase 3/metabolism ; Cells, Cultured ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Humans ; Microcirculation/drug effects ; Neovascularization, Physiologic/drug effects ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors ; Receptors, Tumor Necrosis Factor, Type I/genetics ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Thrombospondin 1/pharmacology ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances CD36 Antigens ; RNA, Messenger ; RNA, Small Interfering ; Receptors, Tumor Necrosis Factor, Type I ; Thrombospondin 1 ; Tumor Necrosis Factor-alpha ; CASP3 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-)
    Language English
    Publishing date 2008-08-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3116-1
    ISSN 1097-4652 ; 0021-9541
    ISSN (online) 1097-4652
    ISSN 0021-9541
    DOI 10.1002/jcp.21570
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Overexpression of FAK promotes Ras activity through the formation of a FAK/p120RasGAP complex in malignant astrocytoma cells.

    Hecker, Timothy P / Ding, Qiang / Rege, Tanya A / Hanks, Steven K / Gladson, Candece L

    Oncogene

    2004  Volume 23, Issue 22, Page(s) 3962–3971

    Abstract: Focal adhesion kinase (FAK) signaling may be mediated through the modulation of Ras activity. We have shown previously that grade III malignant astrocytoma biopsy samples exhibit elevated levels of FAK, and that overexpression of FAK in U-251MG malignant ...

    Abstract Focal adhesion kinase (FAK) signaling may be mediated through the modulation of Ras activity. We have shown previously that grade III malignant astrocytoma biopsy samples exhibit elevated levels of FAK, and that overexpression of FAK in U-251MG malignant astrocytoma cells promotes the phosphorylation of Shc, a potential upstream mediator of Ras activity. Here, we report that overexpression of FAK promotes Ras activity in U-251MG malignant astrocytoma cells cultured in aggregate suspension or as monolayers adherent to vitronectin. The overexpression of FAK also promoted the association of FAK with p120RasGAP, which is a negative regulator of Ras activity, in the U-251MG cells cultured in aggregate suspension, with this association being abrogated upon plating of the cells onto vitronectin. An association of FAK with p120RasGAP also was observed in malignant astrocytoma biopsy samples, but not in normal brain samples. As overexpression of FAK in U-251MG cells in aggregate suspension culture reduced the amount of p120RasGAP complexed with active Ras, we hypothesize that the association of FAK with p120 RasGAP may facilitate Ras activity. The overexpression of a mutated FAK in which the Y397 had been mutated to F did not result in the formation of the FAK/p120RasGAP complex and did not promote Ras activity, indicating that the Y397 residue of FAK plays a role in the formation of this complex and in the activation of Ras. Moreover, the overexpression of mutated FAK (397F) was found to inhibit anchorage-independent growth. These data provide the basis for a previously undescribed mechanism in which the elevated expression of FAK can promote Ras activity through its competitive recruitment of p120RasGAP, thereby diminishing the association of p120RasGAP with active Ras.
    MeSH term(s) Animals ; Astrocytoma/metabolism ; Cell Division/physiology ; Focal Adhesion Kinase 1 ; Focal Adhesion Protein-Tyrosine Kinases ; Guanosine Triphosphate/metabolism ; Humans ; Protein-Tyrosine Kinases/metabolism ; Rats ; p120 GTPase Activating Protein/metabolism ; ras Proteins/metabolism
    Chemical Substances p120 GTPase Activating Protein ; Guanosine Triphosphate (86-01-1) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Focal Adhesion Kinase 1 (EC 2.7.10.2) ; Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2) ; PTK2 protein, human (EC 2.7.10.2) ; Ptk2 protein, rat (EC 2.7.10.2) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2004-05-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/sj.onc.1207541
    Database MEDical Literature Analysis and Retrieval System OnLINE

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