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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-02-0567.
Submitted February 21, 2003
Accepted July 3, 2003
Granulocyte-macrophage colony-stimulating factor and interleukin 3 induce cell cycle progression through the synthesis of c-Myc protein by internal ribosome entry site-mediated translation via phosphatidylinositol 3-kinase pathway in human factor-dependent leukemic cells
Norihiko Kobayashi, Kumiko Saeki, and Akira Yuo*
Department of Hematology, Research Institute, International Medical Center of Japan, Tokyo, Japan
Japan Society for the Promotion of Science, Japan
* Corresponding author; email: yuoakira{at}ri.imcj.go.jp.
To investigate the roles of c-myc during hematopoietic proliferation induced by growth factors, we used factor-dependent human leukemic cell lines (MO7e and F36P) in which proliferation, cell cycle progression and c-Myc expression were strictly regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). In these cell lines, both c-myc mRNA and c-Myc protein stability were not affected by GM-CSF and IL-3, suggesting a regulation of c-Myc protein at the translational level. However, rapamycin, an inhibitor of cap-dependent translation, did not block c-myc induction by GM-CSF and IL-3. Thus, we studied the cap-independent translation, the internal ribosome entry site (IRES), during c-Myc protein synthesis using dicistronic reporter gene plasmids, and found that GM-CSF and IL-3 activated c-myc IRES to initiate translation. c-myc IRES activation, c-Myc protein expression and cell cycle progression were all blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. In another factor-dependent cell line UT7, we observed the cell cycle progression and upregulation of c-Myc protein, c-myc mRNA and c-myc IRES simultaneously, which were all inhibited by LY294002. Results indicate that hematopoietic growth factors induce cell cycle progression via IRES-mediated translation of c-myc though the PI3K pathway in human factor-dependent leukemic cells.
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