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

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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
Author(s)
Mi-Kyung Yoon; B Y Kim; J Y 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; J Song; Sung Goo ParkByoung Chul ParkKwang-Hee Bae; S U Choi; Seung-Wook Chi
Bibliographic Citation
Journal of Biological Chemistry, vol. 293, no. 51, pp. 19546-19558
Publication Year
2018
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, DNA fragmentation, GST pulldown, and apoptosis 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. We observed that the α-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-apoptotic BH3 peptides. 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.
ISSN
0021-9258
Publisher
Amer Soc Biochemistry Molecular Biology Inc
DOI
http://dx.doi.org/10.1074/jbc.RA118.003061
Type
Article
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
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