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      Brk tyrosine kinase signaling in the gastrointestinal tract

      , Prof. Dr. (Referee), , Prof. (Referee), , Prof. Dr. (Referee)

      Mathematisch-Naturwissenschaftliche Fakultät I, Humboldt-Universität

      Biologie, Biowissenschaften, Biologie, WD 5060, Brk, Sik, PTK6, Tyrosine Kinase, Darmepithel, Brk, Sik, PTK6, Protein tyrosine kinase, intestine

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          Abstract

          Die Tyrosin Kinase Brk stellt den Prototypen nicht N-terminal myristoylierter, Nicht-Rezeptor Tyrosin Kinasen dar. Die Expression dieser Kinase ist auf epitheliale Gewebe beschränkt und wird während der Entwicklung differentiell reguliert. In normalen Geweben ist die Brk Expression auf nichtproliferierende, terminal differenzierte Zellen beschränkt. Um die regulatorische Funktion von Brk im murinen Darmepithel zu untersuchen, wurde das brk Gen in der Maus inaktiviert. Brk knockout Mäuse zeigten keine offensichtlichen Defekte in ihrer Entwicklung jedoch eine erweiterte Proliferationszone in den Krypten des Darmepithels und verlängerte Villi. Die Inaktivierung von Brk führte zu einer erhöhten Akkummulation von nukleärem (-catenin sowie einer Hochregulierung des (-catenin Zielgens c-myc in den Krypten der knockout Mäuse. Zusätzlich zeigten Brk knockout Mäuse eine Aktivierung des Akt-Signaltransduktionswegs in ihrem Darmepithel. Im Gegensatz zu Wildtyp Mäusen waren Brk knockout Mäuse resistent gegenüber (-Strahlung, was die Anhäufung onkogener Mutationen und damit die Entwicklung von Krebs fördert. Eine Induktion der Expression des Brk-Proteins im Darmepithel behandelter Wildtyp Mäuse wurde festgestellt. Weiterhin traten bei Brk knockout Mäusen chronische Entzündungen des Darmepithels sowie eine erhöhte Sensibilität gegenüber dem Reizmittel DSS auf. Im Gegensatz dazu, zeigten Wildtyp Mäuse eine mit der Literatur Übereinstimmende Reaktion zu DSS verbunden mit einer Induktion der Brk Expression im Darmepithel. Zusammenfassend kann gesagt werden, dass die Brk Tyrosin Kinase eine entscheidende Rolle in der Aufrechterhaltung der Homöstase und Integrität des Darmepithels spielt. Insbesondere scheint Brk als wichtiger Faktor zur Bestimmung der Sensitivität epithelialer Zellen zu genotoxischem Stress zu fungieren. Entgegen der bisher vermuteten onkogenen Funktion in epithelialen Tumoren scheint Brk im normalen Darmepithel "Tumor Suppressor" Ähnliche Funtionen innezuhaben.

          Abstract

          The Breast tumor kinase Brk is a prototypical non-myristoylated, non-receptor tyrosine kinase. Brk expression is epithelial-specific and ,in normal tissues, restricted to cells exiting the cell cycle and undergoing terminal differentiation. To determine the biological role of Brk in the gastrointestinal tract, we disrupted mouse brk by homologous recombination. Loss of Brk in the mouse resulted in increased intestinal epithelial cell turnover and the appearance of longer small intestinal villi. Brk deficient mice displayed enhanced accumulation of nuclear (-catenin and upregulation of the (-catenin target gene c-myc in the crypt compartment of small and large intestine. In addition, Brk deficient mice exhibited increased Akt kinase activity. Even though, there was no corresponding difference in base-line apoptosis in untreated wild-type and knockout animals. However, subjected to (-irradiation, Brk deficient animals were significantly impaired in the apoptotic response. Wild-type mice, however, exhibited normal levels of apoptosis following (-irradiation accompanied by a rapid induction of Brk expression in crypt cells. Furthermore, chronic inflammation was observed in Brk deficient mice, and they showed increased susceptibility to a colon injury model utilizing DSS. Interestingly, wild-type mice exhibited a significant upregulation of nuclear Brk protein throughout the intestinal epithelium in response to DSS. These recent findings suggest that Brk plays a crucial role in the maintenance of intestinal tissue homeostasis and integrity. In addition, Brk may function to protect the intestinal epithelium against DNA-replication-induced errors and hence the development of cancer. Contrary to reported oncogenic properties of Brk in other epithelial tissues, Brk appears to have tumor suppressor-like functions in the mouse gastrointestinal epithelium.

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          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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              Single step method of RNA isolation by acid guanidium thiocyanate phenol chloroform extraction. Anal

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                Author and article information

                Journal
                Mathematisch-Naturwissenschaftliche Fakultät I, Humboldt-Universität (kvv )
                5 January 2006
                Article
                oai:HUBerlin.de:26421

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