TPA-induced p21 expression augments G2/M arrest through a p53-independent             mechanism in human breast cancer cells.
The tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), has a differential             role on the regulation of the cell cycle in a variety of tumor cells. The mechanism             between TPA and the cell cycle in breast cancer is not fully understood. Therefore,             we investigated the regulatory mechanism of TPA on control of the cell cycle of             breast cancer cells. Our results showed that TPA increased the level of p21 expression             in MCF-7 cells with wild-type p53 and MDA-MB-231 cells with mutant p53 in a dose-dependent             manner. In contrast, TPA decreased the expression of p53 in MCF-7 cells, but did             not affect MDA-MB-231 cells. We next examined the regulatory mechanism of TPA             on p21 and p53 expression. Our results showed that the TPA-induced up-regulation             of p21 and down-regulation of p53 was reversed by UO126 (a MEK1/2 inhibitor),             but not by SP600125 (a JNK inhibitor) or SB203580 (a p38 inhibitor), although             TPA increased the phosphorylation of ERK and JNK in MCF-7 cells. In addition,             the TPA-induced arrest of the G2/M phase was also recovered by UO126 treatment.             To confirm the expression of p21 through the MEK/ERK pathway, cells were transfected             with constitutively active (CA)-MEK adenovirus. Our results showed that the expression             of p21 was significantly increased by CA-MEK overexpression. Taken together, we             suggest that TPA reciprocally regulates the level of p21 and p53 expression via             a MEK/ERK-dependent pathway. The up-regulation of p21 in response to TPA is mediated             through a p53-independent mechanism in breast cancer cells.
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, Republic of Korea.
Jeonghun
J
Han
Sangmin
S
Kim
Jung-Hyun
JH
Yang
Seok Jin
SJ
Nam
Jeong Eon
JE
Lee
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D002070:Butadienes; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C113580:U 0126; D013755:Tetradecanoylphorbol Acetate