Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas

Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf ) tumour suppressors 1 , 2 . Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-r...

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Veröffentlicht in:	Nature (London) Jg. 428; H. 6980; S. 337 - 341
Hauptverfasser:	Leung, Carly, Lingbeek, Merel, Shakhova, Olga, Liu, James, Tanger, Ellen, Saremaslani, Parvin, van Lohuizen, Maarten, Marino, Silvia
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 18.03.2004 Nature Publishing Nature Publishing Group
Schlagworte:	Animals Biological and medical sciences Bmi1 gene Cell culture Cell Division Cerebellum - cytology Cerebellum - embryology Cerebellum - metabolism Gene Deletion Gene expression Gene Expression Regulation, Developmental Gene Expression Regulation, Neoplastic Hedgehog Proteins Humanities and Social Sciences Humans Intracellular Signaling Peptides and Proteins letter Leukemia Medical sciences medulloblastoma Medulloblastoma - genetics Medulloblastoma - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Knockout multidisciplinary Neurology Neurophysiology Nuclear Proteins - genetics Nuclear Proteins - metabolism Oncogene Proteins - genetics Oncogene Proteins - metabolism Patched Receptors Patched-1 Receptor Pathology Phenotype Polycomb Repressive Complex 1 Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Receptors, Cell Surface Repressor Proteins RNA, Messenger - genetics RNA, Messenger - metabolism Science Science (multidisciplinary) Signal Transduction sonic hedgehog protein Stem Cells - cytology Stem Cells - metabolism Trans-Activators - metabolism Transcription Factors - genetics Transcription Factors - metabolism tumor suppressor genes Tumors Tumors of the nervous system. Phacomatoses Zinc Finger Protein GLI1 Cerebellum Human Cell proliferation Cell culture Granule neuron Stem cell Leukemia Rodentia Precursor cell Gene overexpression In vitro Vertebrata Mammalia Mouse Medulloblastoma Development Tumor
ISSN:	0028-0836, 1476-4687, 1476-4687
Online-Zugang:	Volltext
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Zusammenfassung:	Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf ) tumour suppressors 1 , 2 . Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated 1 , 3 . Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1 -null mice we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro . Deregulated proliferation of these progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to medulloblastoma development 4 . We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, these findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for Bmi1-containing polycomb complexes in proliferation of cerebellar precursor cells.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/nature02385