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.