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rdf:type |
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lifeskim:mentions |
umls-concept:C0004561,
umls-concept:C0035820,
umls-concept:C0044602,
umls-concept:C0123771,
umls-concept:C0205464,
umls-concept:C0285761,
umls-concept:C0314603,
umls-concept:C0486379,
umls-concept:C0542341,
umls-concept:C0597298,
umls-concept:C0683941,
umls-concept:C1150481,
umls-concept:C1368105,
umls-concept:C1451005,
umls-concept:C1514762,
umls-concept:C1554080,
umls-concept:C1705325,
umls-concept:C1706198,
umls-concept:C2346501
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pubmed:issue |
2
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pubmed:dateCreated |
2006-1-10
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pubmed:abstractText |
Mouse gene-targeting studies have documented a central role of the p110delta isoform of phosphoinositide 3-kinase (PI3K) in B-cell development and function. A defect in B-cell antigen receptor (BCR) signaling is key to this B-cell phenotype. Here we further characterize this signaling defect and report that a p110delta-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110delta in BCR signaling. p110delta activity is indispensable for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B (PKB), forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase (p70 S6K), with modest effects on the phosphorylation of glycogen synthase kinase 3 alpha/beta (GSK3alpha/beta) and extracellular signal-regulated kinase (Erk). The PI3K-dependent component of intracellular calcium mobilization also completely relies on p110delta catalytic activity. Resting B cells with inactive p110delta fail to enter the cell cycle, correlating with an incapacity to up-regulate the expression of cyclins D2, A, and E, and to phosphorylate the retinoblastoma protein (Rb). p110delta is also critical for interleukin 4 (IL-4)-induced phosphorylation of Akt/PKB and FOXO3a, and protection from apoptosis. Taken together, these data show that defects observed in p110delta mutant mice are not merely a consequence of altered B-cell differentiation, and emphasize the potential utility of p110delta as a drug target in autoimmune diseases in which B cells play a crucial role.
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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 |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CCND2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin A,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin E,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/FOXO3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Forkhead Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Glycogen Synthase Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-4,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pik3cd protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Isoforms,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Antigen, B-Cell,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Interleukin-4,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoblastoma Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Ribosomal Protein S6 Kinases, 70-kDa,
http://linkedlifedata.com/resource/pubmed/chemical/glycogen synthase kinase 3 alpha,
http://linkedlifedata.com/resource/pubmed/chemical/glycogen synthase kinase 3 beta
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0006-4971
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
107
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
642-50
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:16179367-Animals,
pubmed-meshheading:16179367-Apoptosis,
pubmed-meshheading:16179367-B-Lymphocytes,
pubmed-meshheading:16179367-Calcium,
pubmed-meshheading:16179367-Cell Cycle,
pubmed-meshheading:16179367-Cell Differentiation,
pubmed-meshheading:16179367-Cell Proliferation,
pubmed-meshheading:16179367-Cyclin A,
pubmed-meshheading:16179367-Cyclin D2,
pubmed-meshheading:16179367-Cyclin E,
pubmed-meshheading:16179367-Cyclins,
pubmed-meshheading:16179367-Enzyme Inhibitors,
pubmed-meshheading:16179367-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:16179367-Female,
pubmed-meshheading:16179367-Forkhead Transcription Factors,
pubmed-meshheading:16179367-Glycogen Synthase Kinase 3,
pubmed-meshheading:16179367-Interleukin-4,
pubmed-meshheading:16179367-Male,
pubmed-meshheading:16179367-Mice,
pubmed-meshheading:16179367-Mice, Inbred C57BL,
pubmed-meshheading:16179367-Mice, Knockout,
pubmed-meshheading:16179367-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:16179367-Phosphorylation,
pubmed-meshheading:16179367-Protein Isoforms,
pubmed-meshheading:16179367-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:16179367-Receptors, Antigen, B-Cell,
pubmed-meshheading:16179367-Receptors, Interleukin-4,
pubmed-meshheading:16179367-Retinoblastoma Protein,
pubmed-meshheading:16179367-Ribosomal Protein S6 Kinases, 70-kDa,
pubmed-meshheading:16179367-Signal Transduction
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pubmed:year |
2006
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pubmed:articleTitle |
Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells.
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pubmed:affiliation |
Ludwig Institute for Cancer Research, 91 Riding House Street, London, W1W 7BS, United Kingdom.
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pubmed:publicationType |
Journal Article
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