| Structural highlights
Function
P73_HUMAN Participates in the apoptotic response to DNA damage. Isoforms containing the transactivation domain are pro-apoptotic, isoforms lacking the domain are anti-apoptotic and block the function of p53 and transactivating p73 isoforms. May be a tumor suppressor protein.[1] [2] [3]
Publication Abstract from PubMed
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 pull-down, 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 alpha-helical p73-TAD16 peptide binds to a non-canonical 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 non-canonical 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.
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 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 J Biol Chem. 2018 Nov 14. pii: RA118.003061. doi: 10.1074/jbc.RA118.003061. PMID:30429221[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Grob TJ, Novak U, Maisse C, Barcaroli D, Luthi AU, Pirnia F, Hugli B, Graber HU, De Laurenzi V, Fey MF, Melino G, Tobler A. Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ. 2001 Dec;8(12):1213-23. PMID:11753569 doi:10.1038/sj.cdd.4400962
- ↑ Kaelin WG Jr. The emerging p53 gene family. J Natl Cancer Inst. 1999 Apr 7;91(7):594-8. PMID:10203277
- ↑ Koida N, Ozaki T, Yamamoto H, Ono S, Koda T, Ando K, Okoshi R, Kamijo T, Omura K, Nakagawara A. Inhibitory role of Plk1 in the regulation of p73-dependent apoptosis through physical interaction and phosphorylation. J Biol Chem. 2008 Mar 28;283(13):8555-63. doi: 10.1074/jbc.M710608200. Epub 2008 , Jan 3. PMID:18174154 doi:10.1074/jbc.M710608200
- ↑ 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. Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL. J Biol Chem. 2018 Nov 14. pii: RA118.003061. doi: 10.1074/jbc.RA118.003061. PMID:30429221 doi:http://dx.doi.org/10.1074/jbc.RA118.003061
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