PTEN/MMAC1 overexpression decreases insulin-like growth factor-I-mediated protection from apoptosis in neuroblastoma cells.
Insulin-like growth factor I (IGF-I) protects cells from apoptosis primarily through the action of phosphatidylinositol-3 kinase and the downstream serine/threonine kinase Akt. The PTEN gene product, a protein which dephosphorylates phosphatidylinositol lipids, prevents activation of Akt and regulates several cellular functions, including cell cycle progression, cell migration, and survival from apoptosis. In this study, PTEN overexpression decreases IGF-I-induced Akt activity, enhances serum withdrawal-induced apoptosis, and decreases IGF-I protection and cell growth in SHEP cells. The PTEN lipid phosphatase mutant G129E fails to inhibit IGF-I-stimulated Akt activity and protection from apoptosis. The C124S mutation, which abolishes both lipid and protein phosphatase activity, fails to inhibit Akt activity and IGF-I protection against hyperosmotic-induced apoptosis but still inhibits growth and IGF-I protection against serum withdrawal-induced apoptosis. These data suggest a role for PTEN in modulating the effect of IGF-I on Akt activity, neuroblastoma cell growth, and protection against apoptotic stimuli.
van Golen
C M
CM
University of Michigan Department of Neurology, Neuroscience Program, Ann Arbor, Michigan 48109, USA.
Schwab
T S
TS
Ignatoski
K M
KM
Ethier
S P
SP
Feldman
E L
EL
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D016895:Culture Media, Serum-Free; D004234:Diuretics, Osmotic / Q000494:pharmacology; D005434:Flow Cytometry; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008353:Mannitol / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D016895:Culture Media, Serum-Free; D004234:Diuretics, Osmotic; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D008353:Mannitol; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase