Linked Life Data

21368228

Source:http://linkedlifedata.com/resource/pubmed/id/21368228

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2011-3-22
pubmed:abstractText
Although the physiological consequences of Notch signaling in hematopoiesis have been extensively studied, the differential effects of individual notch cleavage products remain to be elucidated. Given that ADAM10 is a critical regulator of Notch and that its deletion is embryonically lethal, we generated mice that overexpress ADAM10 (ADAM10 transgenic [A10Tg]) at early stages of lympho- and myeloid development. Transgene expression resulted in abrogated B cell development, delayed T cell development in the thymus, and unexpected systemic expansion of CD11b(+)Gr-1(+) cells, also known as myeloid-derived suppressor cells. Mixed bone marrow reconstitution assays demonstrated that transgene expression altered hematopoiesis via a cell-intrinsic mechanism. Consistent with previously reported observations, we hypothesized that ADAM10 overexpression dysregulated Notch by uncoupling the highly regulated proteolysis of Notch receptors. This was confirmed using an in vitro model of hematopoiesis via culturing A10Tg hematopoietic Lineage(-)Sca-1(+)c-Kit(+) cells with OP-9 stromal cells in the presence or absence of Delta-like 1, a primary ligand for Notch. Blockade of the site 2 (S2) and site 3 (S3) cleavage of the Notch receptor demonstrated differential effects on hematopoiesis. OP9-DL1 cultures containing the ADAM10 inhibitor (S2 cleavage site) enhanced and rescued B cell development from wild-type and A10Tg Lineage(-)Sca-1(+)c-Kit(+) cells, respectively. In contrast, blockade of ?-secretase at the S3 cleavage site induced accumulation of the S2 product and consequently prevented B cell development and resulted in myeloid cell accumulation. Collectively, these findings indicate that the differential cleavage of Notch into S2 and S3 products regulated by ADAM10 is critical to hematopoietic cell-fate determination.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1550-6606
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
186
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4244-52
pubmed:meshHeading
pubmed-meshheading:21368228-ADAM Proteins, pubmed-meshheading:21368228-Amyloid Precursor Protein Secretases, pubmed-meshheading:21368228-Animals, pubmed-meshheading:21368228-B-Lymphocytes, pubmed-meshheading:21368228-Cell Lineage, pubmed-meshheading:21368228-Cell Proliferation, pubmed-meshheading:21368228-Cells, Cultured, pubmed-meshheading:21368228-Growth Inhibitors, pubmed-meshheading:21368228-Hematopoietic Stem Cells, pubmed-meshheading:21368228-Hydrolysis, pubmed-meshheading:21368228-Lymphopoiesis, pubmed-meshheading:21368228-Membrane Proteins, pubmed-meshheading:21368228-Mice, pubmed-meshheading:21368228-Mice, Inbred C57BL, pubmed-meshheading:21368228-Mice, Transgenic, pubmed-meshheading:21368228-Multipotent Stem Cells, pubmed-meshheading:21368228-Myeloid Progenitor Cells, pubmed-meshheading:21368228-Myelopoiesis, pubmed-meshheading:21368228-Receptors, Notch, pubmed-meshheading:21368228-Signal Transduction, pubmed-meshheading:21368228-Thymus Gland
pubmed:year
2011
pubmed:articleTitle
ADAM10 overexpression shifts lympho- and myelopoiesis by dysregulating site 2/site 3 cleavage products of Notch.
pubmed:affiliation
Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, School of Medicine, Richmond, VA 23298, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural