PKC pathway and ERK/MAPK pathway are required for induction of cyclin D1 and p21Waf1 during 12-o-tetradecanoylphorbol 13-acetate-induced differentiation of myeloleukemia cells.
Treatment of human promyelocytic leukemia cell HL60 with 12-o-tetradecanoylphorbol 13-acetate (TPA) induces growth arrest, differentiation towards the monocyte/macrophage lineage, and expression of cell cycle-regulating genes cyclin D1 and p21Waf1. First, we demonstrated that p21Waf1 expression was increased by TPA in other leukemia cell lines also, including THP-1, U937, and KG-1, which differentiate into monocytes/macrophages by TPA. Secondly, we demonstrated the signal transduction pathways of cyclin D1 and p21Waf1 expressions in TPA-treated HL60 cells. Induction of cyclin D1 expression in TPA-treated HL60 cells was inhibited with protein kinase C (PKC) inhibitor bisindolylmaleimide I and mitogen activated protein kinase kinase (MEK) inhibitor PD98059. Induction of p21Waf1 expression in TPA-treated HL60 cells was inhibited with PKC inhibitor bisindolylmaleimide I and Gö6976, MEK inhibitor PD98059, and p38 mitogen-actibated protein kinase (MAPK) inhibitor SB202190. Thus, cyclin D1 and p21Waf1 expressions are considered to be induced via PKC and extracellular signal-regulated kinase/mitogen-activated protein kinase (MAPK/ERK) pathways in TPA-treated HL60 cells. The upregulation of p21Waf1 seems to play a critical role in TPA-induced cell differentiation by suppressing cyclin dependent kinase activity , while the upregulation of cyclin D1 seems to be compensated by p21Waf1.
Matsumoto
Eriko
E
Department of Medical Technology, Kobe-Tokiwa College, Kobe, Japan. ematsumoto@kobe-tokiwa.ac.jp
Hatanaka
Michiyo
M
Bohgaki
Miyako
M
Maeda
Sakan
S
D002454:Cell Differentiation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D011493:Protein Kinase C / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019938:Cyclin D1; D003513:Cycloheximide; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate