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Molecular and Cellular Biology, August 2007, p. 5819-5834, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.02422-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

PML-Retinoic Acid Receptor Inhibits PML IV Enhancement of PU.1-Induced C/EBP Expression in Myeloid Differentiation ^,

Hitoshi Yoshida,^1* Hitoshi Ichikawa,² Yusuke Tagata,¹ Takuo Katsumoto,¹ Kazunori Ohnishi,³ Yukihiro Akao,⁴ Tomoki Naoe,⁵ Pier Paolo Pandolfi,⁶ and Issay Kitabayashi¹

Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan,¹ Cancer Transcriptome Project, National Cancer Center Research Institute, Tokyo, Japan,² Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan,³ Department of Genetic Diagnosis, Gifu International Institute of Biotechnology, Kakamigahara, Japan,⁴ Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan,⁵ Cancer Biology and Genetics Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York⁶

Received 28 December 2006/ Returned for modification 23 January 2007/ Accepted 17 May 2007

PML and PU.1 play important roles in myeloid differentiation. PML-deficient mice have an impaired capacity for terminal maturation of their myeloid precursor cells. This finding has been explained, at least in part, by the lack of PML action to modulate retinoic acid-differentiating activities. In this study, we found that C/EBP expression is reduced in PML-deficient mice. We showed that PU.1 directly activates the transcription of the C/EBP gene that is essential for granulocytic differentiation. The type IV isoform of PML interacted with PU.1, promoted its association with p300, and then enhanced PU.1-induced transcription and granulocytic differentiation. In contrast to PML IV, the leukemia-associated PML-retinoic acid receptor fusion protein dissociated the PU.1/PML IV/p300 complex and inhibited PU.1-induced transcription. These results suggest a novel pathogenic mechanism of the PML-retinoic acid receptor fusion protein in acute promyelocytic leukemia.

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* Corresponding author. Mailing address: Molecular Oncology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-Chome, Chuo-Ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511, ext. 4752. Fax: 81-3-3542-0688. E-mail: hityoshi{at}gan2.res.ncc.go.jp

Published ahead of print on 11 June 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, August 2007, p. 5819-5834, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.02422-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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