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J. Biol. Chem., Vol. 277, Issue 12, 9936-9943, March 22, 2002

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Up-regulation of Acid Sphingomyelinase during Retinoic Acid-induced Myeloid Differentiation of NB4, a Human Acute Promyelocytic Leukemia Cell Line^*

Takashi Murate^§, Motoshi Suzuki^¶, Masashi Hattori^¶, Akira Takagi, Tetsuhito Kojima, Tomomi Tanizawa^¶, Haruhiko Asano, Tomomitsu Hotta^**, Hidehiko Saito, Shonen Yoshida^¶, and Keiko Tamiya-Koizumi^¶

From the  Nagoya University School of Health Science, ^¶ Research Institute for Disease Mechanism and Control,  The First Department of Internal Medicine, Nagoya University Graduate School & Faculty of Medicine, Nagoya 466-8550, Japan and the ^** The Fourth Department of Internal Medicine, Tokai University School of Medicine, Isehara 259-1100 Japan

All-trans-retinoic acid (ATRA) induces myeloid differentiation of a human promyelocytic leukemia cell line, NB4, but does not affect its subclone NB4/RA harboring a point-mutated ligand-binding domain (AF2) in retinoic acid receptor  (RAR) gene. We found that ATRA induced the 4-fold elevation of acid sphingomyelinase (ASMase) activity 24 h after treatment in NB4 cells, but not in NB4/RA cells. ATRA did not affect neutral sphingomyelinase activity in either NB4 or NB4/RA. Upon treatment with ATRA, ceramide, the product of an ASMase reaction, accumulated in NB4 cells. Northern blot analysis showed a marked elevation of the ASMase mRNA 8 h after ATRA treatment, reaching a plateau at 24 h. Regulation of ASMase gene expression was studied by a promoter analysis using luciferase reporter assay. The 5'-upstream flanking region of human ASMase gene (519/+300) conjugated with the luciferase gene was introduced into COS-7 cells. Luciferase activity in transformed cells markedly increased in response to ATRA stimulation when the wild type RAR or the PML/RAR hybrid protein was co-expressed. Deletion experiments revealed that a short sequence at the 5'-end (519/485) was indispensable for the ATRA response. Within this short region, two retinoic acid-responsive element-like motifs (TGCCCG and TCTCCT) and one AP2-like motif (CCCTTCCC) were identified. Deletion and base-substitution experiments showed that all three motifs are required for the full expression induced by ATRA. Electrophoresis mobility shift assays with the nuclear extract of ATRA-treated NB4 cells showed that proteins were bound specifically to the probe being mediated by all three motifs in the promoter sequence.

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