BH3-only activator proteins Bid and Bim are dispensable for Bak/Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency molecular requisites for the mitochondrial pathway to apoptosis in platelets

Takahiro Kodama, Tetsuo Takehara, Hayato Hikita, Satoshi Shimizu, Minoru Shigekawa, Wei Li, Takuya Miyagi, Atsushi Hosui, Tomohide Tatsumi, Hisashi Ishida, Tatsuya Kanto, Naoki Hiramatsu, Xiao-Ming Yin, Norio Hayashi

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Abstract

A pivotal step in the mitochondrial pathway of apoptosis is activation of Bak and Bax, although the molecular mechanism remains controversial. To examine whether mitochondrial apoptosis can be induced by just a lack of antiapoptotic Bcl-2-like proteins or requires direct activators of the BH3-only proteins including Bid and Bim, we studied the molecular requisites for platelet apoptosis induced by Bcl-xL deficiency. Severe thrombocytopenia induced by thrombocyte-specific Bcl-xL knock-out was fully rescued in a Bak and Bax double knock-out background but not with single knock-out of either one. In sharp contrast, deficiency of either Bid, Bim, or both did not alleviate thrombocytopenia in Bcl-xL knock-out mice. An in vitro study revealed that ABT-737, a Bad mimetic, induced platelet apoptosis in association with a conformational change of the amino terminus, translocation from the cytosol to mitochondria, and homo-oligomerization of Bax. ABT-737-induced Bax activation and apoptosis were also observed in Bid/Bim-deficient platelets. Human platelets, upon storage, underwent spontaneous apoptosis with a gradual decline of Bcl-xL expression despite a decrease in Bid and Bim expression. Apoptosis was attenuated in Bak/Bax-deficient or Bcl-xL-overexpressing platelets but not in Bid/Bim-deficient platelets upon storage. In conclusion, platelet lifespan is regulated by a fine balance between anti-and proapoptotic multidomain Bcl-2 family proteins. Despite residing in platelets, BH3-only activator proteins Bid and Bim are dispensable for Bax activation and mitochondrial apoptosis.

Original languageEnglish
Pages (from-to)13905-13913
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number16
DOIs
StatePublished - Apr 22 2011

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BH3 Interacting Domain Death Agonist Protein
Platelets
Blood Platelets
Apoptosis
Chemical activation
Thrombocytopenia
Oligomerization
Proteins
Mitochondria
Knockout Mice
Cytosol
Association reactions

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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BH3-only activator proteins Bid and Bim are dispensable for Bak/Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency molecular requisites for the mitochondrial pathway to apoptosis in platelets. / Kodama, Takahiro; Takehara, Tetsuo; Hikita, Hayato; Shimizu, Satoshi; Shigekawa, Minoru; Li, Wei; Miyagi, Takuya; Hosui, Atsushi; Tatsumi, Tomohide; Ishida, Hisashi; Kanto, Tatsuya; Hiramatsu, Naoki; Yin, Xiao-Ming; Hayashi, Norio.

In: Journal of Biological Chemistry, Vol. 286, No. 16, 22.04.2011, p. 13905-13913.

Research output: Contribution to journalArticle

Kodama, T, Takehara, T, Hikita, H, Shimizu, S, Shigekawa, M, Li, W, Miyagi, T, Hosui, A, Tatsumi, T, Ishida, H, Kanto, T, Hiramatsu, N, Yin, X-M & Hayashi, N 2011, 'BH3-only activator proteins Bid and Bim are dispensable for Bak/Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency molecular requisites for the mitochondrial pathway to apoptosis in platelets', Journal of Biological Chemistry, vol. 286, no. 16, pp. 13905-13913. https://doi.org/10.1074/jbc.M110.195370
Kodama, Takahiro ; Takehara, Tetsuo ; Hikita, Hayato ; Shimizu, Satoshi ; Shigekawa, Minoru ; Li, Wei ; Miyagi, Takuya ; Hosui, Atsushi ; Tatsumi, Tomohide ; Ishida, Hisashi ; Kanto, Tatsuya ; Hiramatsu, Naoki ; Yin, Xiao-Ming ; Hayashi, Norio. / BH3-only activator proteins Bid and Bim are dispensable for Bak/Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency molecular requisites for the mitochondrial pathway to apoptosis in platelets. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 16. pp. 13905-13913.
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T1 - BH3-only activator proteins Bid and Bim are dispensable for Bak/Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency molecular requisites for the mitochondrial pathway to apoptosis in platelets

AU - Kodama, Takahiro

AU - Takehara, Tetsuo

AU - Hikita, Hayato

AU - Shimizu, Satoshi

AU - Shigekawa, Minoru

AU - Li, Wei

AU - Miyagi, Takuya

AU - Hosui, Atsushi

AU - Tatsumi, Tomohide

AU - Ishida, Hisashi

AU - Kanto, Tatsuya

AU - Hiramatsu, Naoki

AU - Yin, Xiao-Ming

AU - Hayashi, Norio

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N2 - A pivotal step in the mitochondrial pathway of apoptosis is activation of Bak and Bax, although the molecular mechanism remains controversial. To examine whether mitochondrial apoptosis can be induced by just a lack of antiapoptotic Bcl-2-like proteins or requires direct activators of the BH3-only proteins including Bid and Bim, we studied the molecular requisites for platelet apoptosis induced by Bcl-xL deficiency. Severe thrombocytopenia induced by thrombocyte-specific Bcl-xL knock-out was fully rescued in a Bak and Bax double knock-out background but not with single knock-out of either one. In sharp contrast, deficiency of either Bid, Bim, or both did not alleviate thrombocytopenia in Bcl-xL knock-out mice. An in vitro study revealed that ABT-737, a Bad mimetic, induced platelet apoptosis in association with a conformational change of the amino terminus, translocation from the cytosol to mitochondria, and homo-oligomerization of Bax. ABT-737-induced Bax activation and apoptosis were also observed in Bid/Bim-deficient platelets. Human platelets, upon storage, underwent spontaneous apoptosis with a gradual decline of Bcl-xL expression despite a decrease in Bid and Bim expression. Apoptosis was attenuated in Bak/Bax-deficient or Bcl-xL-overexpressing platelets but not in Bid/Bim-deficient platelets upon storage. In conclusion, platelet lifespan is regulated by a fine balance between anti-and proapoptotic multidomain Bcl-2 family proteins. Despite residing in platelets, BH3-only activator proteins Bid and Bim are dispensable for Bax activation and mitochondrial apoptosis.

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