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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3731-3738.
Prepublished online as a Blood First Edition Paper on August 12, 2004; DOI 10.1182/blood-2004-04-1630.
 Previous Article | Next Article 
Submitted April 30, 2004
Accepted July 23, 2004
Protein kinase C  mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation
Ke-Wen Zhao, Xi Li, Qian Zhao, Ying Huang, Dong Li, Zhen-Gang Peng, Wu-Zhong Shen, Ji Zhao, Quansheng Zhou, Zhu Chen, Peter J Sims, Therese Wiedmer, and Guo-Qiang Chen*
Health Science Center, Shanghai Second Medical University (SSMU) -Shanghai Institutes for Biological Sciences and Graduate School of the Chinese Academy of Sciences, shanghai, China
Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, shanghai, China
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
Health Science Center, Shanghai Second Medical University (SSMU) -Shanghai Institutes for Biological Sciences and Graduate School of the Chinese Academy of Sciences, shanghai, China; Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, shanghai, China
* Corresponding author; email: chengq{at}shsmu.edu.cn.
Although phospholipid scramblase 1 (PLSCR1) was originally identified based on its capacity to promote transbilayer movement of membrane phospholipids, subsequent studies also provided evidence for its roles in cell proliferation, maturation, and apoptosis. In this report we investigate the potential role of PLSCR1 in leukemic cell differentiation. We show that all-trans retinoic acid (ATRA), an effective differentiation-inducing agent of acute promyelocytic leukemic (APL) cells, can elevate PLSCR1 expression in ATRA-sensitive APL cells NB4 and HL60, but not in ATRA-resistant NB4-LR1 cells. ATRA- and PMA-induced monocytic differentiation of U937 cells is accompanied by increased PLSCR1 expression, whereas only a slight or no elevation of PLSCR1 expression is observed in cells differentiated with DMSO, sodium butyrate, or vitamin D3. Cell differentiation with ATRA and PMA, but not with vitamin D3 or DMSO, results in phosphorylation of protein kinase C (PKC), and the PKC-specific inhibitor rottlerin nearly eliminates the ATRA- and PMA-induced expression of PLSCR1, while ectopic expression of a constitutively active form of PKC directly increases PLSCR1 expression. Finally, decreasing PLSCR1 expression with small interfering RNA inhibits ATRA/PMA-induced differentiation. Taken together, these results suggest that as a protein induced upon PKC activation, PLSCR1 is required for ATRA and PMA-triggered leukemic cell differentiation.
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