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Molecular and Cellular Biology, September 2004, p. 8236-8243, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8236-8243.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Brap2 Functions as a Cytoplasmic Retention Protein for p21 during Monocyte Differentiation

Minoru Asada,1,2,{dagger} Kazuhiro Ohmi,3 Domenico Delia,4 Shin Enosawa,5 Seiichi Suzuki,5 Akira Yuo,2 Hidenori Suzuki,6,{dagger} and Shuki Mizutani1*

Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University,1 Department of Pharmacology, Nippon Medical School, Bunkyo-ku,6 Department of Hematology, Research Institute, International Medical Center of Japan, Shinjuku-ku,2 Department of Pathology,3 Department of Surgery, National Children's Medical Research Center, Setagaya-ku, Tokyo, Japan,5 Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy4

Received 15 December 2003/ Returned for modification 16 January 2004/ Accepted 10 June 2004

The cell cycle inhibitor p21 plays an important role in monocytic cell differentiation, during which it translocates from the nucleus to cytoplasm. This process involves the negative regulation of the p21 nuclear localization signal (NLS). Here, we sought to determine the relationship between the cytoplasmic translocation of p21 and another molecule, Brap2, a cytoplasmic protein which binds the NLS of BRCA1 and was recently reported to inactivate KSR in the Ras-activating signal pathway under the name of IMP. We report that p21 and Brap2 directly interact, both in vitro and in vivo, in a manner requiring the NLS of p21 and the C-terminal portion of Brap2. When it is cotransfected with Brap2, p21 is expressed in the cytoplasm. Monocytic differentiation of the promyelomonocytic cell lines U937 and HL60 is associated with the upregulation of Brap2 expression concomitantly with the upregulation and cytoplasmic relocalization of p21. Our results underscore the role played by Brap2 in the process of cytoplasmic translocation of p21 during monocyte differentiation.

* Corresponding author. Mailing address: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: 81-3-5803-5244. Fax: 81-3-3818-7181. E-mail: smizutani.ped{at}tmd.ac.jp.

{dagger} Present address: Department of Pharmacology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.

Molecular and Cellular Biology, September 2004, p. 8236-8243, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.8236-8243.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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