Differentiation-inducing factor-1-induced growth arrest of K562 leukemia cells involves the reduction of ERK1/2 activity.
The differentiation-inducing factor-1 (DIF-1) is a signal molecule that induces stalk cell differentiation in the cellular slime mold Dictyostelium discoideum. In addition, DIF-1 is a potent antileukemic agent that induces growth arrest in K562 cells. In this study, we investigated the mechanism of action of DIF-1 in K562 cells in the light of cell-cycle regulators such as cyclins, retinoblastoma protein (pRb), and the mitogen-activated protein kinase (MAPK) family. DIF-1 down-regulated cyclins D/E and a phosphorylated form of pRb (p-pRb), and thereby induced G(1) arrest of the cell cycle. DIF-1 inactivated the extracellular signal-regulated kinase (ERK) in a biphasic manner but did not affect the c-Jun N-terminal kinase (JNK) or p38 MAPK. The MEK (MAPK kinase) inhibitor, U0126, which has been shown to induce growth arrest, inactivated ERK and down-regulated cyclins D and E. Although DIF-1 activated the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway, neither wortmannin nor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002; PI-3K inhibitors) cancelled DIF-1-induced growth arrest. The present results suggest that ERK inactivation may be involved in DIF-1-induced growth arrest and that PI-3K activity is not required for DIF-1-induced growth arrest in K562 cells.
Akaishi
Emi
E
Department of Basic Sciences for Medicine, Gunma University School of Health Sciences, Maebashi 371-8514, Japan.
Narita
Torao
T
Kawai
Shinjiro
S
Miwa
Yoshikazu
Y
Sasaguri
Toshiyuki
T
Hosaka
Kohei
K
Kubohara
Yuzuru
Y
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006588:Hexanones; D006801:Humans; D006843:Hydrocarbons, Chlorinated; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology / Q000517:prevention & control; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011506:Proteins
D000970:Antineoplastic Agents; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C490570:Differentiation-inducing factor-1, Dictyostelium; D004791:Enzyme Inhibitors; D006588:Hexanones; D006843:Hydrocarbons, Chlorinated; D011506:Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases