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 Dec 21

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yoon, M. K., Kim, B. Y., Lee, J. Y., Ha, J. H., Kim, S. A., Lee, D. H., Lee, M. S., Lee, M. K., Choi, J. S., Cho, J. H., Kim, J. H., Kim, S., Song, J., Park, S. G., Park, B. C., Bae, K. H., Choi, S. U., & Chi, S. W. (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, 293(51), 19546-19558. https://doi.org/10.1074/jbc.RA118.003061