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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
2004-5-4
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pubmed:abstractText |
Mammalian presenilins (PS) consist of two highly homologous proteins, PS1 and PS2. Because of their indispensable activity in the gamma-secretase cleavage of amyloid precursor protein to generate Abeta peptides, inhibition of PS gamma-secretase activity is considered a potential therapy for Abeta blockage and Alzheimer's disease intervention. However, a variety of other substrates are also subject to PS-dependent processing, and it is thus imperative to understand the consequences of PS inactivation in vivo. Here we report a pivotal role of PS in hematopoiesis. Mice heterozygous for PS1 and homozygous for PS2 (PS1(+/)(-)PS2(-)(/)(-)) developed splenomegaly with severe granulocyte infiltration. This was preceded by an overrepresentation of granulocytic cells in the bone marrow and a greatly increased multipotent granulocyte-monocyte progenitor in the spleen. In contrast, hematopoietic stem cells and T- and B-lymphocytes were not affected. Importantly, treatment of wild-type splenocytes with a gamma-secretase inhibitor directly promoted the granulocyte-macrophage colony-forming unit (GM-CFU). These results establish a critical role of PS in myelopoiesis. Our finding that this activity can be directly modulated by its gamma-secretase activity has important safety implications concerning these inhibitors.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0006-2960
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
43
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5352-9
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15122901-Amyloid Precursor Protein Secretases,
pubmed-meshheading:15122901-Animals,
pubmed-meshheading:15122901-Aspartic Acid Endopeptidases,
pubmed-meshheading:15122901-Cell Lineage,
pubmed-meshheading:15122901-Colony-Forming Units Assay,
pubmed-meshheading:15122901-Endopeptidases,
pubmed-meshheading:15122901-Female,
pubmed-meshheading:15122901-Gene Dosage,
pubmed-meshheading:15122901-Granulocytes,
pubmed-meshheading:15122901-Hematopoiesis,
pubmed-meshheading:15122901-Leukocyte Count,
pubmed-meshheading:15122901-Macrophages,
pubmed-meshheading:15122901-Male,
pubmed-meshheading:15122901-Membrane Proteins,
pubmed-meshheading:15122901-Mice,
pubmed-meshheading:15122901-Mice, Inbred C57BL,
pubmed-meshheading:15122901-Mice, Knockout,
pubmed-meshheading:15122901-Myeloproliferative Disorders,
pubmed-meshheading:15122901-Presenilin-1,
pubmed-meshheading:15122901-Presenilin-2,
pubmed-meshheading:15122901-Protease Inhibitors
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pubmed:year |
2004
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pubmed:articleTitle |
Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage.
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pubmed:affiliation |
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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