Original Article

Oncogene (2007) 26, 1522–1532. doi:10.1038/sj.onc.1209962; published online 11 September 2006

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

A Tsuchiya1, E Tashiro1, M Yoshida2 and M Imoto1

  1. 1Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan
  2. 2Chemical Genetics Laboratory, RIKEN, Wako, Saitama, Japan

Correspondence: Professor M Imoto, Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyohi, Kohoku-ku, Yokohama 223-8522, Japan. E-mail: imoto@bio.keio.ac.jp

Received 3 April 2006; Revised 20 June 2006; Accepted 6 July 2006; Published online 11 September 2006.



Leptomycin B (LMB) is a Streptomyces metabolite that causes the specific inhibition of the nuclear export of proteins containing a nuclear export signal (NES). LMB was reported to inhibit cell cycle progression in fission yeast and mammalian cells, however, the mechanism underlying LMB-induced cell cycle arrest is still obscure. In this study, we found that in serum-starved NIH3T3 cells, LMB inhibited serum-induced cyclin D1 expression at the level of transcription. However, this inhibition was reversed by inhibitors of protein phosphatase 2A (PP2A). Furthermore, we found that PP2A accumulated in the nucleus upon treatment with LMB. The finding prompted us to identify the functional NES in PP2A catalytic subunit alpha. These results indicated that LMB inhibited the chromosomal region maintenance 1 (CRM1)-dependent nuclear export of PP2A, resulting in sustained dephosphorylation in the nucleus. Although phosphorylation of c-Jun at Ser-63 is required for activator protein 1 (AP-1)-dependent expression of cyclin D1, it decreased in LMB-treated cells compared to untreated cells. Moreover, the inhibitors of PP2A restored the levels of c-Jun phosphorylated at Ser-63. We propose that inhibition of cyclin D1 expression by LMB is mediated by the LMB-induced nuclear accumulation of PP2A, leading to sustained dephosphorylation of c-Jun at Ser-63, which leads to inactivation of the transcription of the AP-1-responsive cyclin D1 gene.


leptomycin B, cyclin D1, PP2A, c-Jun



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