Role of nucleophosmin in embryonic development and tumorigenesis
Nucleophosmin (also known as NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders. Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo h...
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| Veröffentlicht in: | Nature 2005-09, Vol.437 (7055), p.147-153 |
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| creator | Grisendi, Silvia Cheng, Ke Rossi, Marco Khandker, Luipa Manova, Katia Pandolfi, Pier Paolo Bernardi, Rosa |
| description | Nucleophosmin (also known as NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders. Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. To study the function of Npm in vivo, we generated a hypomorphic Npm1 mutant series (Npm1+/- < Npm1hy/hy < Npm1-/-) in mouse. Here we report that Npm is essential for embryonic development and the maintenance of genomic stability. Npm1-/- and Npm1hy/hy mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. We show that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis. |
| doi_str_mv | 10.1038/nature03915 |
| format | Article |
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Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. To study the function of Npm in vivo, we generated a hypomorphic Npm1 mutant series (Npm1+/- < Npm1hy/hy < Npm1-/-) in mouse. Here we report that Npm is essential for embryonic development and the maintenance of genomic stability. Npm1-/- and Npm1hy/hy mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. We show that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature03915</identifier><identifier>PMID: 16007073</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Apoptosis - genetics ; Cell Cycle - genetics ; Cell Transformation, Neoplastic - genetics ; Cell Transformation, Neoplastic - pathology ; Cells, Cultured ; Centrosome - metabolism ; Embryo Loss - genetics ; Embryonic Development ; Embryonic growth stage ; Embryos ; Fibroblasts ; Gene Deletion ; Genomic Instability - genetics ; Hematology ; Hematopoiesis - genetics ; Humanities and Social Sciences ; In Situ Hybridization, Fluorescence ; Inactivation ; letter ; Mice ; Mice, Knockout ; multidisciplinary ; Myelodysplastic Syndromes - genetics ; Myelodysplastic Syndromes - pathology ; Neoplasms - genetics ; Neoplasms - metabolism ; Neoplasms - pathology ; Nuclear Proteins - deficiency ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Pathogens ; Prenatal development ; Science ; Science (multidisciplinary) ; Tumors</subject><ispartof>Nature, 2005-09, Vol.437 (7055), p.147-153</ispartof><rights>Springer Nature Limited 2005</rights><rights>COPYRIGHT 2005 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 1, 2005</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c612t-4d7b50e2759be30c8057f0c8eb46f03afc1d41da8e1bc76506a4577676ddcd053</citedby><cites>FETCH-LOGICAL-c612t-4d7b50e2759be30c8057f0c8eb46f03afc1d41da8e1bc76506a4577676ddcd053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature03915$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature03915$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,2727,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16007073$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grisendi, Silvia</creatorcontrib><creatorcontrib>Cheng, Ke</creatorcontrib><creatorcontrib>Rossi, Marco</creatorcontrib><creatorcontrib>Khandker, Luipa</creatorcontrib><creatorcontrib>Manova, Katia</creatorcontrib><creatorcontrib>Pandolfi, Pier Paolo</creatorcontrib><creatorcontrib>Bernardi, Rosa</creatorcontrib><title>Role of nucleophosmin in embryonic development and tumorigenesis</title><title>Nature</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Nucleophosmin (also known as NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders. 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We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis.</description><subject>Animals</subject><subject>Apoptosis - genetics</subject><subject>Cell Cycle - genetics</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Cells, Cultured</subject><subject>Centrosome - metabolism</subject><subject>Embryo Loss - genetics</subject><subject>Embryonic Development</subject><subject>Embryonic growth stage</subject><subject>Embryos</subject><subject>Fibroblasts</subject><subject>Gene Deletion</subject><subject>Genomic Instability - genetics</subject><subject>Hematology</subject><subject>Hematopoiesis - genetics</subject><subject>Humanities and Social Sciences</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Inactivation</subject><subject>letter</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>multidisciplinary</subject><subject>Myelodysplastic Syndromes - 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Academic</collection><jtitle>Nature</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grisendi, Silvia</au><au>Cheng, Ke</au><au>Rossi, Marco</au><au>Khandker, Luipa</au><au>Manova, Katia</au><au>Pandolfi, Pier Paolo</au><au>Bernardi, Rosa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of nucleophosmin in embryonic development and tumorigenesis</atitle><jtitle>Nature</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2005-09-01</date><risdate>2005</risdate><volume>437</volume><issue>7055</issue><spage>147</spage><epage>153</epage><pages>147-153</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Nucleophosmin (also known as NPM, B23, NO38) is a nucleolar protein directly implicated in cancer pathogenesis, as the NPM1 gene is found mutated and rearranged in a number of haematological disorders. Furthermore, the region of chromosome 5 to which NPM1 maps is deleted in a proportion of de novo human myelodysplastic syndromes (MDS), and loss of chromosome 5 is extremely frequent in therapy-related MDS. NPM is a multifunctional protein, and its role in oncogenesis is controversial as NPM has been attributed with both oncogenic and tumour suppressive functions. To study the function of Npm in vivo, we generated a hypomorphic Npm1 mutant series (Npm1+/- < Npm1hy/hy < Npm1-/-) in mouse. Here we report that Npm is essential for embryonic development and the maintenance of genomic stability. Npm1-/- and Npm1hy/hy mutants have aberrant organogenesis and die between embryonic day E11.5 and E16.5 owing to severe anaemia resulting from defects in primitive haematopoiesis. We show that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. We demonstrate that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1+/- mice develop a haematological syndrome with features of human MDS. Our findings uncover an essential developmental role for Npm and implicate its functional loss in tumorigenesis and MDS pathogenesis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>16007073</pmid><doi>10.1038/nature03915</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Apoptosis - genetics Cell Cycle - genetics Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - pathology Cells, Cultured Centrosome - metabolism Embryo Loss - genetics Embryonic Development Embryonic growth stage Embryos Fibroblasts Gene Deletion Genomic Instability - genetics Hematology Hematopoiesis - genetics Humanities and Social Sciences In Situ Hybridization, Fluorescence Inactivation letter Mice Mice, Knockout multidisciplinary Myelodysplastic Syndromes - genetics Myelodysplastic Syndromes - pathology Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Nuclear Proteins - deficiency Nuclear Proteins - genetics Nuclear Proteins - metabolism Pathogens Prenatal development Science Science (multidisciplinary) Tumors |
| title | Role of nucleophosmin in embryonic development and tumorigenesis |
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