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BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling 总被引:21,自引:0,他引:21
He XC Zhang J Tong WG Tawfik O Ross J Scoville DH Tian Q Zeng X He X Wiedemann LM Mishina Y Li L 《Nature genetics》2004,36(10):1117-1121
In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number. 相似文献
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Zhang J Grindley JC Yin T Jayasinghe S He XC Ross JT Haug JS Rupp D Porter-Westpfahl KS Wiedemann LM Wu H Li L 《Nature》2006,441(7092):518-522
Haematopoietic stem cells (HSCs) must achieve a balance between quiescence and activation that fulfils immediate demands for haematopoiesis without compromising long-term stem cell maintenance, yet little is known about the molecular events governing this balance. Phosphatase and tensin homologue (PTEN) functions as a negative regulator of the phosphatidylinositol-3-OH kinase (PI(3)K)-Akt pathway, which has crucial roles in cell proliferation, survival, differentiation and migration. Here we show that inactivation of PTEN in bone marrow HSCs causes their short-term expansion, but long-term decline, primarily owing to an enhanced level of HSC activation. PTEN-deficient HSCs engraft normally in recipient mice, but have an impaired ability to sustain haematopoietic reconstitution, reflecting the dysregulation of their cell cycle and decreased retention in the bone marrow niche. Mice with PTEN-mutant bone marrow also have an increased representation of myeloid and T-lymphoid lineages and develop myeloproliferative disorder (MPD). Notably, the cell populations that expand in PTEN mutants match those that become dominant in the acute myeloid/lymphoid leukaemia that develops in the later stages of MPD. Thus, PTEN has essential roles in restricting the activation of HSCs, in lineage fate determination, and in the prevention of leukaemogenesis. 相似文献
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He XC Yin T Grindley JC Tian Q Sato T Tao WA Dirisina R Porter-Westpfahl KS Hembree M Johnson T Wiedemann LM Barrett TA Hood L Wu H Li L 《Nature genetics》2007,39(2):189-198
Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector beta-catenin. Akt phosphorylates beta-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of beta-catenin. 相似文献
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Wiedemann N Kozjak V Chacinska A Schönfisch B Rospert S Ryan MT Pfanner N Meisinger C 《Nature》2003,424(6948):565-571
Mitochondria contain translocases for the transport of precursor proteins across their outer and inner membranes. It has been assumed that the translocases also mediate the sorting of proteins to their submitochondrial destination. Here we show that the mitochondrial outer membrane contains a separate sorting and assembly machinery (SAM) that operates after the translocase of the outer membrane (TOM). Mas37 forms a constituent of the SAM complex. The central role of the SAM complex in the sorting and assembly pathway of outer membrane proteins explains the various pleiotropic functions that have been ascribed to Mas37 (refs 4, 11-15). These results suggest that the TOM complex, which can transport all kinds of mitochondrial precursor proteins, is not sufficient for the correct integration of outer membrane proteins with a complicated topology, and instead transfers precursor proteins to the SAM complex. 相似文献
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E. Wiedemann 《Cellular and molecular life sciences : CMLS》1947,3(9):341-353
Zusammenfassung Es wird ein Überblick über die Elektrophorese gegeben, wie sie aus den grundlegenden Arbeiten vonA. Tiselius-hervorgegangen und vonL. G. Longsworth, H. Svensson und anderen Forschern ausgebaut worden ist. Neuere Fortschritte der Technik und Methodik, die in Amerika, Schweden und der Schweiz erzielt werden konnten und sowohl eine Erleichterung der Versuche wie eine Steigerung der Meßgenauigkeit ermöglichen, werden besprochen. Die Bedeutung der Elektrophorese, insbesondere für die Proteinforschung, wird hervorgehoben und es wird auf die zunehmende Verbreitung der Elektrophorese hingewiesen, die sich in einem erheblichen Anwachsen der einschlägigen Literatur spiegelt. Leistungsfähigkeit und Anwendungsbereich der Elektrophorese werden umrissen mit dem Hinweis darauf, daß es zumeist von Vorteil ist, die Ergebnisse mit Hilfe anderer geeigneter Methoden (Ultrazentrifugierung, Diffusionsmessung usw.) zu sichern, zu ergänzen und zu erweitern.
Originally delivered by the author in the form of two lectures one on the 20th November 1946 (Naturforschende, Chemische und Medizinische Gesellschaft Basel) and the other on the 16th January 1947 (Chemische Gesellschaft, Biochemische Vereinigung und Ärzteverein Bern). 相似文献
Originally delivered by the author in the form of two lectures one on the 20th November 1946 (Naturforschende, Chemische und Medizinische Gesellschaft Basel) and the other on the 16th January 1947 (Chemische Gesellschaft, Biochemische Vereinigung und Ärzteverein Bern). 相似文献
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Zhang J Niu C Ye L Huang H He X Tong WG Ross J Haug J Johnson T Feng JQ Harris S Wiedemann LM Mishina Y Li L 《Nature》2003,425(6960):836-841
Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche'--the in vivo regulatory microenvironment where HSCs reside--and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin+CD45- osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and beta-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size. 相似文献
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