Multiple signaling pathways are involved in the regulation of IGF-I receptor inhibition of PTEN-enhanced apoptosis.
PTEN is a dual protein and lipid phosphatase that dephosphorylates PIP3 at the 3' position, thereby antagonizing PI3-kinase activity. A reduction in PI3' kinase activity enhances the susceptibility of cells to apoptosis. By stably transfecting PC12 cells with an antisense PTEN construct, endogenous PTEN protein levels were reduced by approximately 50% and etoposide-induced apoptosis was markedly decreased. Furthermore, IGF-I receptor abrogation of this apoptotic effect was inhibited by both PI3' kinase and by specific inhibitors of p38 MAP kinase. Thus, we show for the first time that p38 MAP kinase is involved in this process.
Wu
Yiping
Y
Chief Diabetes Branch, Room 8D12, Bldg 10, Bethesda, MD 20892-1758, USA.
Karas
Michael
M
Dupont
Joelle
J
Zhao
Hong
H
Toyoshima
Yuka
Y
Le Roith
Derek
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D016373:DNA, Antisense / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016716:PC12 Cells; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D002867:Chromones; D016373:DNA, Antisense; D004791:Enzyme Inhibitors; D005047:Etoposide; D007093:Imidazoles; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C487216:Pten protein, rat; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole