Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

BH4-domain peptide from Bcl-xL exerts anti-apoptotic activity in vivo

Oncogene volume 22, pages 8432–8440 (2003)Cite this article

Abstract

The Bcl-2 family of proteins regulates apoptosis chiefly by controlling mitochondrial membrane permeability. It has previously been shown that the BH4 domain of Bcl-2/Bcl-xL is essential for the prevention of apoptotic mitochondrial changes, including the release of cytochrome c and apoptotic cell death. We have previously reported that BH4 peptide fused to the protein transduction domain of HIV-1 TAT protein (TAT-BH4) significantly inhibits etoposide-induced apoptosis in a cell line. This time, we investigated whether TAT-BH4 peptide was cytoprotective in ex vivo and in vivo rodent models. Intraperitoneal injection of TAT-BH4 peptide greatly inhibited X-ray-induced apoptosis in the small intestine of mice and partially suppressed Fas-induced fulminant hepatitis. In addition, this peptide markedly suppressed heart failure after ischemia–reperfusion injury in isolated rat heart, probably by preventing mitochondrial dysfunction. These findings demonstrate that TAT-BH4 peptide exerts anti-apoptotic activity both in vivo and ex vivo, and imply that it may be a useful therapeutic agent for diseases involving mitochondrial dysfunction and apoptosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Abbreviations

BH:

Bcl-2 homology

PTD:

protein transduction domain

VDAC:

voltage-dependent anion channel

RCR:

respiratory control ratio

mAST:

mitochondrial aspartate aminotransferase

References

  • Adams JM and Cory S . (1998). Science, 281, 1322–1326.

  • Borner C, Martinou I, Mattmann C, Irmler M, Schaerer E, Martinou JC and Tschopp J . (1994). J. Cell Biol., 126, 1059–1068.

  • Du C, Fang M, Li Y, Li L and Wang X . (2000). Cell, 102, 33–42.

  • Eskes R, Desagher S, Antonsson B and Martinou JC . (2000). Mol. Cell. Biol., 20, 929–935.

  • Green DR and Reed JC . (1998). Science, 281, 1309–1312.

  • Hanada M, Aime-Sempe C, Sato T and Reed JC . (1995). J. Biol. Chem., 270, 11962–11969.

  • Hirotani M, Zhang Y, Fujita N, Naito M and Tsuruo T . (1999). J. Biol. Chem., 274, 20415–20420.

  • Hockenbery DM . (1992). Semin. Immunol., 4, 413–420.

  • Huang DC, Adams JM and Cory S . (1998). EMBO J., 17, 1029–1039.

  • Hunter JJ, Bond BL and Parslow TG . (1996). Mol. Cell. Biol., 16, 877–883.

  • Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR and Newmeyer DD . (2002). Cell, 111, 331–342.

  • Lee LC, Hunter JJ, Mujeeb A, Turck C and Parslow TG . (1996). J. Biol. Chem., 271, 23284–23288.

  • Macho A, Calzado MA, Jimenez-Reina L, Ceballos E, Leon J and Munoz E . (1999). Oncogene, 18, 7543–7551.

  • Martinou JC and Green DR . (2001). Nat. Rev. Mol. Cell Biol., 2, 63–67.

  • Niwa H, Yamamura K and Miyazaki J . (1991). Gene, 108, 193–199.

  • Oltvai ZN, Milliman CL and Korsmeyer SJ . (1993). Cell, 74, 609–619.

  • Park IW, Ullrich CK, Schoenberger E, Ganju RK and Groopman JE . (2001). J. Immunol., 167, 2766–2771.

  • Saikumar P, Dong Z, Weinberg JM and Venkatachalam MA . (1998). Oncogene, 17, 3341–3349.

  • Saito M, Korsmeyer SJ and Schlesinger PH . (2000). Nat. Cell Biol., 2, 553–555.

  • Schwarze SR, Hruska KA and Dowdy SF . (2000). Trends Cell Biol., 10, 290–295.

  • Schwarze SR, Ho A, Vocero-Akbani A and Dowdy SF . (1999). Science, 285, 1569–1572.

  • Shibasaki F, Kondo E, Akagi T and McKeon F . (1997). Nature, 386, 728–731.

  • Shimizu S, Kamiike W, Hatanaka N, Nishimura M, Miyata M, Inoue T, Yoshida Y, Tagawa K and Matsuda H . (1994). Transplantation, 57, 144–148.

  • Shimizu S, Eguchi Y, Kamiike W, Itoh Y, Hasegawa J, Yamabe K, Otsuki Y, Matsuda H and Tsujimoto Y . (1996a). Cancer Res., 56, 2161–2166.

  • Shimizu S, Eguchi Y, Kamiike W, Matsuda H and Tsujimoto Y . (1996b). Oncogene, 12, 2251–2257.

  • Shimizu S, Narita M and Tsujimoto Y . (1999). Nature, 399, 483–487.

  • Shimizu S, Ide T, Yanagida T and Tsujimoto Y . (2000a). J. Biol. Chem., 275, 12321–12325.

  • Shimizu S, Konishi A, Kodama T and Tsujimoto Y . (2000b). Proc. Natl. Acad. Sci. USA, 97, 3100–3105.

  • Shimizu S, Matsuoka Y, Shinohara Y, Yoneda Y and Tsujimoto Y . (2001). J. Cell Biol., 152, 237–250.

  • Solem LE and Wallace KB . (1993). Toxicol. Appl. Pharmacol., 121, 50–57.

  • Suzuki K, Sawa Y, Kaneda Y, Ichikawa H, Shirakura R and Matsuda H . (1997). J. Clin. Invest., 99, 1645–1650.

  • Tsujimoto Y and Shimizu S . (2000a). FEBS Lett., 466, 6–10.

  • Tsujimoto Y and Shimizu S . (2000b). Cell Death Differ., 7, 1174–1181.

  • Tsujimoto Y . (2003). J. Cell. Physiol., 195, 158–167.

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL . (2000). Cell, 102, 43–53.

  • Wang HG, Rapp UR and Reed JC . (1996). Cell, 87, 629–638.

  • Wang X . (2001). Genes Dev., 15, 2922–2933.

  • Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB and Korsmeyer SJ . (2000). Genes Dev., 14, 2060–2071.

  • Yamabe K, Shimizu S, Kamiike W, Waguri S, Eguchi Y, Hasegawa J, Okuno S, Yoshioka Y, Ito T, Sawa Y, Uchiyama Y, Tsujimoto Y and Matsuda H . (1998). Biochem. Biophys. Res. Commun., 243, 217–223.

  • Yang E, Zha J, Jockel J, Boise LH, Thompson CB and Korsmeyer SJ . (1995). Cell, 80, 285–291.

  • Zamzami N and Kroemer G . (2001). Nat. Rev. Mol. Cell Biol., 2, 67–71.

Download references

Acknowledgements

This study was supported in part by a grant for Scientific Research on Priority Areas, a grant for Center of Excellence Research, a grant for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and by Special Coordination Funds of Promoting Science and Technology from the Science and Technology Agency of Japan.

Author information

Authors and Affiliations

  1. Department of Post-Genomics & Diseases, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Rie Sugioka, Shigeomi Shimizu & Yoshihide Tsujimoto

  2. CREST and SORST of Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Rie Sugioka, Shigeomi Shimizu & Yoshihide Tsujimoto

  3. Department of Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Toshihiro Funatsu, Hiroshi Tamagawa & Yoshiki Sawa

  4. Laboratory of Protein Architectonics, Research Center for Structural Biology, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Toru Kawakami

Authors
  1. Rie Sugioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigeomi Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihiro Funatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroshi Tamagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiki Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toru Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshihide Tsujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshihide Tsujimoto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugioka, R., Shimizu, S., Funatsu, T. et al. BH4-domain peptide from Bcl-xL exerts anti-apoptotic activity in vivo. Oncogene 22, 8432–8440 (2003). https://doi.org/10.1038/sj.onc.1207180

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207180

Keywords

This article is cited by

Search

Advanced search

Quick links