TEL/platelet-derived growth factor receptor beta activates phosphatidylinositol 3 (PI3) kinase and requires PI3 kinase to regulate the cell cycle.
TEL/platelet-derived growth factor receptor beta (PDGF beta R) is the protein product of the t(5;12) translocation in chronic myelomonocytic leukemia. TEL/PDGF beta R transforms interleukin-3 (IL-3)-dependent Ba/F3 and 32D cells to IL-3 independence and induces a murine myeloproliferative disease in a bone marrow transplantation model of leukemogenesis. The fusion protein encodes a constitutively activated, cytoplasmic tyrosine kinase that activates multiple signal transduction pathways. To identify the signaling pathways that are necessary for transformation by TEL/PDGF beta R, transformed Ba/F3 and 32D cells were studied. TEL/PDGF beta R activates the kinase activity of phosphatidylinositol-3 (PI3) kinase and stimulates phosphorylation of its downstream substrates, including Akt and p70S6 kinase. Activation of this pathway requires the kinase activity of TEL/PDGF beta R and is inhibited by the PDGF beta R inhibitor, STI571. Furthermore, inhibition of PI3 kinase with the pharmacologic inhibitor, LY294002, inhibits growth of the transformed cells. Treated cells arrest in the G1 phase of the cell cycle within 16 hours but do not undergo apoptosis. To study the mechanism of cell cycle arrest by LY294002, the activity of the cdk4 complex, which regulates the transit of cells from the G1 to S phase in hematopoietic cells, was examined. Both STI571 and LY294002 lead to a decrease in the activity of cdk4 kinase activity and a decrease in expression of both Cyclin D2 and Cyclin E within several hours. These studies demonstrate the presence of a signaling pathway from TEL/PDGF beta R to PI3 kinase and subsequently to regulation of the cdk4 kinase complex. Activation of this pathway is necessary for transformation by TEL/PDGF beta R.
Dierov
Jamil
J
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Xu
Qing
Q
Dierova
Raia
R
Carroll
Martin
M
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007399:Interphase / Q000187:drug effects; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins; D015290:Second Messenger Systems / Q000187:drug effects; D014162:Transfection
D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C120888:TEL-PDGFRbeta fusion protein, human; D019869:Phosphatidylinositol 3-Kinases; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases