Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL

Mi Kyung Yoon, Bu Yeon Kim, Ji Young Lee, Ji Hyang Ha, Sung Ah Kim, Dong Hwa Lee, Min Sung Lee, Mi Kyung Lee, Jin Sun Choi, Jin Hwa Cho, Jeong Hoon Kim, Sunhong Kim, Jaewhan Song, Sung Goo Park, Byoung Chul Park, Kwang Hee Bae, Sang Un Choi, Seung Wook Chi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

In response to genotoxic stress, the tumor suppressor protein p73 induces apoptosis and cell cycle arrest. Despite extensive studies on p73-mediated apoptosis, little is known about the cytoplasmic apoptotic function of p73. Here, using H1299 lung cancer cells and diverse biochemical approaches, including colony formation,DNAfragmentation,GSTpulldown,andapoptosis assays along with NMR spectroscopy, we show that p73 induces transcription-independent apoptosis via its transactivation domain (TAD) through a mitochondrial pathway and that this apoptosis is mediated by the interaction between p73- TAD and the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL or BCL2L1). This binding disrupted an interaction between Bcl-XL and the pro-apoptotic protein BH3-interacting domain death agonist (Bid). In particular, we found that a 16-mer p73-TAD peptide motif (p73-TAD16) mediates transcription-independent apoptosis, accompanied by cytochrome c release from the mitochondria, by interacting with Bcl-XL. Interestingly, the structure of the Bcl-XL-p73-TAD16 peptide complex revealed a novel mechanism of Bcl-XL recognition by p73-TAD.Weobserved that theα-helical p73-TAD16 peptide binds to a noncanonical site in Bcl-XL, comprising the BH1, BH2, and BH3 domains in an orientation opposite to those of pro-apoptoticBH3peptides. Taken together, our results indicate that the cytoplasmic apoptotic function of p73 is mediated through a noncanonical mode of Bcl-XL recognition. This finding sheds light on a critical transcription-independent, p73-mediated mechanism for apoptosis induction, which has potential implications for anticancer therapy.

Original languageEnglish
Pages (from-to)19546-19558
Number of pages13
JournalJournal of Biological Chemistry
Volume293
Issue number51
DOIs
Publication statusPublished - 2018 Jan 1

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Tumors
Apoptosis
Transcriptional Activation
Transcription
Neoplasms
Apoptosis Regulatory Proteins
Cells
Peptides
Tumor Suppressor Proteins
Mitochondria
B-Cell Lymphoma
Cell Cycle Checkpoints
Cytochromes c
Nuclear magnetic resonance spectroscopy
DNA Damage
Assays
Lung Neoplasms
Magnetic Resonance Spectroscopy
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yoon, Mi Kyung ; Kim, Bu Yeon ; Lee, Ji Young ; Ha, Ji Hyang ; Kim, Sung Ah ; Lee, Dong Hwa ; Lee, Min Sung ; Lee, Mi Kyung ; Choi, Jin Sun ; Cho, Jin Hwa ; Kim, Jeong Hoon ; Kim, Sunhong ; Song, Jaewhan ; Park, Sung Goo ; Park, Byoung Chul ; Bae, Kwang Hee ; Choi, Sang Un ; Chi, Seung Wook. / Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 51. pp. 19546-19558.
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title = "Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL",
abstract = "In response to genotoxic stress, the tumor suppressor protein p73 induces apoptosis and cell cycle arrest. Despite extensive studies on p73-mediated apoptosis, little is known about the cytoplasmic apoptotic function of p73. Here, using H1299 lung cancer cells and diverse biochemical approaches, including colony formation,DNAfragmentation,GSTpulldown,andapoptosis assays along with NMR spectroscopy, we show that p73 induces transcription-independent apoptosis via its transactivation domain (TAD) through a mitochondrial pathway and that this apoptosis is mediated by the interaction between p73- TAD and the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL or BCL2L1). This binding disrupted an interaction between Bcl-XL and the pro-apoptotic protein BH3-interacting domain death agonist (Bid). In particular, we found that a 16-mer p73-TAD peptide motif (p73-TAD16) mediates transcription-independent apoptosis, accompanied by cytochrome c release from the mitochondria, by interacting with Bcl-XL. Interestingly, the structure of the Bcl-XL-p73-TAD16 peptide complex revealed a novel mechanism of Bcl-XL recognition by p73-TAD.Weobserved that theα-helical p73-TAD16 peptide binds to a noncanonical site in Bcl-XL, comprising the BH1, BH2, and BH3 domains in an orientation opposite to those of pro-apoptoticBH3peptides. Taken together, our results indicate that the cytoplasmic apoptotic function of p73 is mediated through a noncanonical mode of Bcl-XL recognition. This finding sheds light on a critical transcription-independent, p73-mediated mechanism for apoptosis induction, which has potential implications for anticancer therapy.",
author = "Yoon, {Mi Kyung} and Kim, {Bu Yeon} and Lee, {Ji Young} and Ha, {Ji Hyang} and Kim, {Sung Ah} and Lee, {Dong Hwa} and Lee, {Min Sung} and Lee, {Mi Kyung} and Choi, {Jin Sun} and Cho, {Jin Hwa} and Kim, {Jeong Hoon} and Sunhong Kim and Jaewhan Song and Park, {Sung Goo} and Park, {Byoung Chul} and Bae, {Kwang Hee} and Choi, {Sang Un} and Chi, {Seung Wook}",
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Yoon, MK, Kim, BY, Lee, JY, Ha, JH, Kim, SA, Lee, DH, Lee, MS, Lee, MK, Choi, JS, Cho, JH, Kim, JH, Kim, S, Song, J, Park, SG, Park, BC, Bae, KH, Choi, SU & Chi, SW 2018, 'Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL', Journal of Biological Chemistry, vol. 293, no. 51, pp. 19546-19558. https://doi.org/10.1074/jbc.RA118.003061

Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL. / Yoon, Mi Kyung; Kim, Bu Yeon; Lee, Ji Young; Ha, Ji Hyang; Kim, Sung Ah; Lee, Dong Hwa; Lee, Min Sung; Lee, Mi Kyung; Choi, Jin Sun; Cho, Jin Hwa; Kim, Jeong Hoon; Kim, Sunhong; Song, Jaewhan; Park, Sung Goo; Park, Byoung Chul; Bae, Kwang Hee; Choi, Sang Un; Chi, Seung Wook.

In: Journal of Biological Chemistry, Vol. 293, No. 51, 01.01.2018, p. 19546-19558.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL

AU - Yoon, Mi Kyung

AU - Kim, Bu Yeon

AU - Lee, Ji Young

AU - Ha, Ji Hyang

AU - Kim, Sung Ah

AU - Lee, Dong Hwa

AU - Lee, Min Sung

AU - Lee, Mi Kyung

AU - Choi, Jin Sun

AU - Cho, Jin Hwa

AU - Kim, Jeong Hoon

AU - Kim, Sunhong

AU - Song, Jaewhan

AU - Park, Sung Goo

AU - Park, Byoung Chul

AU - Bae, Kwang Hee

AU - Choi, Sang Un

AU - Chi, Seung Wook

PY - 2018/1/1

Y1 - 2018/1/1

N2 - In response to genotoxic stress, the tumor suppressor protein p73 induces apoptosis and cell cycle arrest. Despite extensive studies on p73-mediated apoptosis, little is known about the cytoplasmic apoptotic function of p73. Here, using H1299 lung cancer cells and diverse biochemical approaches, including colony formation,DNAfragmentation,GSTpulldown,andapoptosis assays along with NMR spectroscopy, we show that p73 induces transcription-independent apoptosis via its transactivation domain (TAD) through a mitochondrial pathway and that this apoptosis is mediated by the interaction between p73- TAD and the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL or BCL2L1). This binding disrupted an interaction between Bcl-XL and the pro-apoptotic protein BH3-interacting domain death agonist (Bid). In particular, we found that a 16-mer p73-TAD peptide motif (p73-TAD16) mediates transcription-independent apoptosis, accompanied by cytochrome c release from the mitochondria, by interacting with Bcl-XL. Interestingly, the structure of the Bcl-XL-p73-TAD16 peptide complex revealed a novel mechanism of Bcl-XL recognition by p73-TAD.Weobserved that theα-helical p73-TAD16 peptide binds to a noncanonical site in Bcl-XL, comprising the BH1, BH2, and BH3 domains in an orientation opposite to those of pro-apoptoticBH3peptides. Taken together, our results indicate that the cytoplasmic apoptotic function of p73 is mediated through a noncanonical mode of Bcl-XL recognition. This finding sheds light on a critical transcription-independent, p73-mediated mechanism for apoptosis induction, which has potential implications for anticancer therapy.

AB - In response to genotoxic stress, the tumor suppressor protein p73 induces apoptosis and cell cycle arrest. Despite extensive studies on p73-mediated apoptosis, little is known about the cytoplasmic apoptotic function of p73. Here, using H1299 lung cancer cells and diverse biochemical approaches, including colony formation,DNAfragmentation,GSTpulldown,andapoptosis assays along with NMR spectroscopy, we show that p73 induces transcription-independent apoptosis via its transactivation domain (TAD) through a mitochondrial pathway and that this apoptosis is mediated by the interaction between p73- TAD and the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL or BCL2L1). This binding disrupted an interaction between Bcl-XL and the pro-apoptotic protein BH3-interacting domain death agonist (Bid). In particular, we found that a 16-mer p73-TAD peptide motif (p73-TAD16) mediates transcription-independent apoptosis, accompanied by cytochrome c release from the mitochondria, by interacting with Bcl-XL. Interestingly, the structure of the Bcl-XL-p73-TAD16 peptide complex revealed a novel mechanism of Bcl-XL recognition by p73-TAD.Weobserved that theα-helical p73-TAD16 peptide binds to a noncanonical site in Bcl-XL, comprising the BH1, BH2, and BH3 domains in an orientation opposite to those of pro-apoptoticBH3peptides. Taken together, our results indicate that the cytoplasmic apoptotic function of p73 is mediated through a noncanonical mode of Bcl-XL recognition. This finding sheds light on a critical transcription-independent, p73-mediated mechanism for apoptosis induction, which has potential implications for anticancer therapy.

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