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Paired-like homeodomain protein ESXR1 possesses a cleavable C-terminal region that inhibits cyclin degradation

Oncogene volume 23, pages 6590–6602 (2004)Cite this article

Abstract

The eukaryotic cell cycle is regulated by sequential activation and inactivation of cyclin–cyclin-dependent kinase (Cdk) complexes. In this work, we screened human cDNAs that can rescue yeast Saccharomyces cerevisiae from lethality caused by ectopic expression of human cyclin E and isolated a cDNA encoding ESXR1, a paired-like homeodomain-containing protein with a unique C-terminal proline-rich repeat region. In adult tissues, ESXR1 is primarily expressed in the testis. We demonstrate that ESXR1 prevents degradation of ubiquitinated cyclins in human cells. Accordingly, elevation of ESXR1 level results in accumulation of cyclin A and cyclin B1 and thereby provokes M-phase arrest. In human cells, the 65-kDa full-length ESXR1 protein is capable of proteolytically processing into N-terminal 45-kDa and C-terminal 20-kDa fragments. The C-terminal fragment, containing a proline-rich repeat region, is localized to the cytoplasm and displays the ability to inhibit cyclin degradation. In contrast, the N-terminal fragment, containing a paired-like homeodomain, is localized exclusively in the nucleus, suggesting that it plays a role in transcription. Our results indicate that proteolytic processing of ESXR1 plays a role in concerted regulation of the cell cycle and transcription in human cells.

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References

  • Aberle H, Bauer A, Stappert J, Kispert A and Kemler R . (1997). EMBO J., 16, 3797–3804.

  • Ashizawa S, Nishizawa H, Yamada M, Higashi H, Kondo T, Ozawa H, Kakita A and Hatakeyama M . (2001). J. Biol. Chem., 276, 11362–11370.

  • Azam M, Lee C, Strehlow I and Schindler C . (1997). Immunity, 6, 691–701.

  • Brandeis M and Hunt T . (1996). EMBO J., 15, 5280–5289.

  • Branford WW, Zhao GQ, Valerius MT, Weinstein M, Birkenmeier EH, Rowe LB and Potter SS . (1997). Mech. Dev., 65, 87–98.

  • Chang DC, Xu N and Luo KQ . (2003). J. Biol. Chem., 278, 37865–37873.

  • den Elzen N and Pines J . (2001). J. Cell Biol., 153, 121–136.

  • DeSalle LM and Pagano M . (2001). FEBS Lett., 490, 179–189.

  • Dulic V, Lees E and Reed SI . (1992). Science, 257, 1958–1961.

  • D'Urso G, Marraccino RL, Marshak DR and Roberts JM . (1990). Science, 250, 786–791.

  • Featherstone C and Russell P . (1991). Nature, 349, 808–811.

  • Fohn LE and Behringer RR . (2001). Genomics, 74, 105–108.

  • Furuno N, den Elzen N and Pines J . (1999). J. Cell Biol., 147, 295–306.

  • Glotzer M, Murray AW and Kirschner MW . (1991). Nature, 349, 132–138.

  • Guadagno TM and Newport JW . (1996). Cell, 84, 73–82.

  • King RW, Deshaies RJ, Peters JM and Kirschner MW . (1996). Science, 274, 1652–1659.

  • Lew DJ, Dulic V and Reed SI . (1991). Cell, 66, 1197–1206.

  • Li Y, Lemaire P and Behringer RR . (1997). Dev. Biol., 188, 85–95.

  • Lundgren K, Walworth N, Booher R, Dembski M, Kirschner M and Beach D . (1991). Cell, 64, 1111–1122.

  • Millar JB, McGowan CH, Lenaers G, Jones R and Russell P . (1991). EMBO J., 10, 4301–4309.

  • Morgan DO . (1995). Nature, 374, 131–134.

  • Mumberg D, Müller R and Funk M . (1994). Nucleic Acids Res., 22, 5767–5768.

  • Naumann M, Nieters A, Hatada EN and Scheidereit C . (1993). Oncogene, 8, 2275–2281.

  • Ninomiya-Tsuji J, Nomoto S, Yasuda H, Reed SI and Matsumoto K . (1991). Proc. Natl. Acad. Sci. USA, 88, 9006–9010.

  • Nurse P . (2000). Cell, 100, 71–78.

  • Sette C, Barchi M, Bianchini A, Conti M, Rossi P and Geremia R . (1999). J. Biol. Chem., 274, 33571–33579.

  • Sherr CJ . (1994). Cell, 79, 551–555.

  • Solomon MJ, Glotzer M, Lee TH, Philippe M and Kirschner MW . (1990). Cell, 63, 1013–1024.

  • Su TT . (2001). Curr. Biol., 11, 467–469.

  • Tedesco D, Lukas J and Reed SI . (2002). Genes Dev., 16, 2946–2957.

  • Weinberg RA . (1995). Cell, 81, 323–330.

  • Yan YT, Stein SM, Ding J, Shen MM and Abate-Shen C . (2000). Mol. Cell. Biol., 20, 661–671.

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Acknowledgements

We thank Dr Kunihiro Matsumoto and Dr Hideyoshi Yokosawa for cDNAs. We also thank Dr Chizuko Umehara and Takao Ueno for technical assistance. This work was supported by grants from the Human Frontier Science Program (HFSP), the Ministry of Education, Science, Sports, and Culture of Japan, and the Virtual Research Institute of Aging of Nippon Boehringer Ingelheim.

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Author notes

  1. Satoshi Ashizawa

    Present address: Michael E DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

Authors and Affiliations

  1. Division of Molecular Oncology, Institute for Genetic Medicine and Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, 060-0815, Japan

    Heita Ozawa, Satoshi Ashizawa, Masanori Naito, Masatomo Yanagihara, Naomi Ohnishi, Hideaki Higashi & Masanori Hatakeyama

  2. Department of Surgery, Kitasato University School of Medicine, Sagamihara, 228-8555, Japan

    Heita Ozawa, Satoshi Ashizawa, Masanori Naito, Masatomo Yanagihara & Akira Kakita

  3. Laboratory of Supramolecular Structure, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, 113-0032, Japan

    Tatsuya Maeda

  4. Laboratory of Animal Cytogenetics, Center for Advanced Science and Technology, Hokkaido University, Sapporo, 060-0810, Japan

    Yoichi Matsuda

  5. Department of Urology, Kawasaki Medical School, Kurashiki, 701-0192, Japan

    Yoshimasa Jo

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  1. Heita Ozawa
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Correspondence to Masanori Hatakeyama.

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Ozawa, H., Ashizawa, S., Naito, M. et al. Paired-like homeodomain protein ESXR1 possesses a cleavable C-terminal region that inhibits cyclin degradation. Oncogene 23, 6590–6602 (2004). https://doi.org/10.1038/sj.onc.1207884

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