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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.
Leukemia. 2004 Nov; 18(11):1839-49.L

Abstract

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+Show Affiliations

Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Hospital Hamburg-Eppendorf, Hamburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15457186

Citation

Horn, S, et al. "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." Leukemia, vol. 18, no. 11, 2004, pp. 1839-49.
Horn S, Endl E, Fehse B, et al. 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. Leukemia. 2004;18(11):1839-49.
Horn, S., Endl, E., Fehse, B., Weck, M. M., Mayr, G. W., & Jücker, M. (2004). 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. Leukemia, 18(11), 1839-49.
Horn S, et al. 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. Leukemia. 2004;18(11):1839-49. PubMed PMID: 15457186.
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TY - JOUR T1 - 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. AU - Horn,S, AU - Endl,E, AU - Fehse,B, AU - Weck,M M, AU - Mayr,G W, AU - Jücker,M, PY - 2004/10/1/pubmed PY - 2004/12/16/medline PY - 2004/10/1/entrez SP - 1839 EP - 49 JF - Leukemia JO - Leukemia VL - 18 IS - 11 N2 - 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. SN - 0887-6924 UR - https://www.unboundmedicine.com/medline/citation/15457186/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_ L2 - https://doi.org/10.1038/sj.leu.2403529 DB - PRIME DP - Unbound Medicine ER -