Document Detail


Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle.
MedLine Citation:
PMID:  15457186     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The inositol 5-phosphatase SHIP (SHIP-1) is a negative regulator of signal transduction in hematopoietic cells and targeted disruption of SHIP in mice leads to a myeloproliferative disorder. We analyzed the effects of SHIP on the human leukemia cell line Jurkat in which expression of endogenous SHIP protein is not detectable. Restoration of SHIP expression in Jurkat cells with an inducible expression system caused a 69% reduction of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) and a 65% reduction of Akt kinase activity, which was associated with reduced phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) (Ser-9) without changing the phosphorylation of Bad (Ser-136), FKHR (Ser-256) or MAPK (Thr-202/Tyr-204). SHIP-expressing Jurkat cells showed an increased transit time through the G1 phase of the cell cycle, but SHIP did not cause a complete cell cycle arrest or apoptosis. Extension of the G1 phase was associated with an increased stability of the cell cycle inhibitor p27(Kip1) and reduced phosphorylation of the retinoblastoma protein Rb at serine residue 780. Our data indicate that restoration of SHIP activity in a human leukemia cell line, which has lost expression of endogenous SHIP, downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle.
Authors:
S Horn; E Endl; B Fehse; M M Weck; G W Mayr; M Jücker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Leukemia     Volume:  18     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-10-26     Completed Date:  2004-12-02     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1839-49     Citation Subset:  IM    
Affiliation:
Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis
Carrier Proteins / metabolism
Cyclin-Dependent Kinase Inhibitor p27
DNA-Binding Proteins / metabolism
Down-Regulation
Enzyme Activation
Forkhead Transcription Factors
G1 Phase*
Glycogen Synthase Kinase 3 / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Jurkat Cells
Leukemia / metabolism*,  pathology
Mitogen-Activated Protein Kinase Kinases / metabolism
Phosphatidylinositol 3-Kinases / metabolism*
Phosphatidylinositol Phosphates / metabolism
Phosphoric Monoester Hydrolases / metabolism*
Phosphorylation
Protein-Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Retinoblastoma Protein
Signal Transduction*
Time Factors
Transcription Factors / metabolism
bcl-Associated Death Protein
src Homology Domains
Chemical
Reg. No./Substance:
0/BAD protein, human; 0/CDKN1B protein, human; 0/Carrier Proteins; 0/DNA-Binding Proteins; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Intracellular Signaling Peptides and Proteins; 0/Phosphatidylinositol Phosphates; 0/Proto-Oncogene Proteins; 0/Retinoblastoma Protein; 0/Transcription Factors; 0/bcl-Associated Death Protein; 0/phosphatidylinositol 3,4,5-triphosphate; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases; EC 3.1.3.-/INPPL1 protein, human; EC 3.1.3.-/Phosphoric Monoester Hydrolases

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