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Molecular and Cellular Biology, November 2002, p. 7581-7592, Vol. 22, No. 21
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.21.7581-7592.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cytosolic Retention of Phosphorylated Extracellular Signal-Regulated Kinase and a Rho-Associated Kinase-Mediated Signal Impair Expression of p21Cip1/Waf1 in Phorbol 12-Myristate-13- Acetate-Induced Apoptotic Cells

Jin-Mei Lai, Sulin Wu, Duen-Yi Huang, and Zee-Fen Chang*

Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, Republic of China

Received 15 March 2002/ Returned for modification 15 April 2002/ Accepted 2 August 2002

In response to treatment with phorbol-12-myristate-13-acetate (PMA), the half-population of erythromyeloblast D2 cells, a cytokine-independent variant of TF-1 cells, displayed adhesion and differentiated into a monocyte/macrophage-like morphology, while the other half-population remained in suspension and underwent apoptosis. Expression of the cell cycle inhibitor p21Cip1/Waf1 was induced after PMA treatment in the adherent cells but not in the proapoptotic cells. We investigated the mechanism responsible for the impairment of p21Cip1/Waf1 induction in PMA-induced proapoptotic cells. We demonstrated that in PMA-induced adherent cells, upregulation of p21Cip1/Waf1 requires the activation and nuclear translocation of phosphorylated extracellular signal-regulated kinase (phospho-ERK). Although ERK was phosphorylated to comparable levels in PMA-induced proapoptotic and adherent cells, nuclear distribution of phospho-ERK was seen only in the adherent, not in the proapoptotic cells. We also found that only PMA-induced proapoptotic cells contained the phosphorylated form of myosin light chain, which is dependent on Rho-associated kinase (ROCK) activation, and that expression of a dominant-active form of ROCK suppressed activation of the p21Cip1/Waf1 promoter during PMA induction. Finally, we demonstrated that inhibition of ROCK restores nuclear distribution of phospho-ERK and activation of p21Cip1/Waf1 expression. Based on these findings, we propose that a ROCK-mediated signal is involved in interfering with the process of ERK-mediated p21Cip1/Waf1 induction in PMA-induced proapoptotic TF-1 and D2 cells.

* Corresponding author. Mailing address: Institute of Biochemistry and Molecular Biology, National Taiwan University, College of Medicine, No. 1 section 1 Jen-Ai Road, Taipei, Taiwan, Republic of China. Phone: 886 2 2312 3456. Fax: 886 2 2395-8904. E-mail: zfchang{at}ha.mc.ntu.edu.tw.

Molecular and Cellular Biology, November 2002, p. 7581-7592, Vol. 22, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.21.7581-7592.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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