p53 has a direct apoptogenic role at the mitochondria - PubMed (original) (raw)
p53 has a direct apoptogenic role at the mitochondria
Motohiro Mihara et al. Mol Cell. 2003 Mar.
Free article
Abstract
p53 induces apoptosis by target gene regulation and transcription-independent signaling. However, a mechanism for the latter was unknown. We recently reported that a fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Here, we provide evidence that p53 translocation to the mitochondria occurs in vivo in irradiated thymocytes. Further, we show that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BclXL and Bcl2 proteins, resulting in cytochrome c release. p53 binds to BclXL via its DNA binding domain. We probe the significance of mitochondrial p53 and show that tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BclXL and promote cytochrome c release. This opens the possibility that mutations might represent "double-hits" by abrogating the transcriptional and mitochondrial apoptotic activity of p53.
Comment in
- p53 and apoptosis: it's not just in the nucleus anymore.
Manfredi JJ. Manfredi JJ. Mol Cell. 2003 Mar;11(3):552-4. doi: 10.1016/s1097-2765(03)00106-0. Mol Cell. 2003. PMID: 12667439 Review.
Similar articles
- WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization.
Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C, Pan H, Kessler H, Pancoska P, Moll UM. Tomita Y, et al. J Biol Chem. 2006 Mar 31;281(13):8600-6. doi: 10.1074/jbc.M507611200. Epub 2006 Jan 26. J Biol Chem. 2006. PMID: 16443602 - Characterization of distinct consecutive phases in non-genotoxic p53-induced apoptosis of Ewing tumor cells and the rate-limiting role of caspase 8.
Kovar H, Jug G, Printz D, Bartl S, Schmid G, Wesierska-Gadek J. Kovar H, et al. Oncogene. 2000 Aug 24;19(36):4096-107. doi: 10.1038/sj.onc.1203780. Oncogene. 2000. PMID: 10962570 - The DNA binding domain of p53 is sufficient to trigger a potent apoptotic response at the mitochondria.
Matissek KJ, Mossalam M, Okal A, Lim CS. Matissek KJ, et al. Mol Pharm. 2013 Oct 7;10(10):3592-602. doi: 10.1021/mp400380s. Epub 2013 Sep 6. Mol Pharm. 2013. PMID: 23968395 - Mechanisms of p53-dependent apoptosis.
Schuler M, Green DR. Schuler M, et al. Biochem Soc Trans. 2001 Nov;29(Pt 6):684-8. doi: 10.1042/0300-5127:0290684. Biochem Soc Trans. 2001. PMID: 11709054 Review. - Structural insights into the transcription-independent apoptotic pathway of p53.
Chi SW. Chi SW. BMB Rep. 2014 Mar;47(3):167-72. doi: 10.5483/bmbrep.2014.47.3.261. BMB Rep. 2014. PMID: 24499665 Free PMC article. Review.
Cited by
- Impact of dietary ingredients on radioprotection and radiosensitization: a comprehensive review.
Islam MM, Sultana N, Liu C, Mao A, Katsube T, Wang B. Islam MM, et al. Ann Med. 2024 Dec;56(1):2396558. doi: 10.1080/07853890.2024.2396558. Epub 2024 Sep 25. Ann Med. 2024. PMID: 39320122 Free PMC article. Review. - A novel amphiphilic squalene-based compound with open-chain polyethers reduces malignant melanoma metastasis in-vitro and in-vivo.
Zhang Y, Bejaoui M, Linh TN, Arimura T, Isoda H. Zhang Y, et al. Cell Commun Signal. 2024 Sep 11;22(1):437. doi: 10.1186/s12964-024-01813-5. Cell Commun Signal. 2024. PMID: 39261954 Free PMC article. - Significance of RCC2, Rac1 and p53 Expression in Breast Infiltrating Ductal Carcinoma; An Immunohistochemical Study.
Hemida AS, Abdelaziz RA, Abd El-Wahed MM, Asaad NY, Serag El-Dien MM, Elshahat Ali HA. Hemida AS, et al. Iran J Pathol. 2024 Spring;19(2):177-192. doi: 10.30699/IJP.2024.2014367.3198. Epub 2023 Feb 15. Iran J Pathol. 2024. PMID: 39118792 Free PMC article. - Pirh2 modulates the mitochondrial function and cytochrome c-mediated neuronal death during Alzheimer's disease.
Singh A, Tiwari S, Singh S. Singh A, et al. Cell Death Dis. 2024 May 13;15(5):331. doi: 10.1038/s41419-024-06662-1. Cell Death Dis. 2024. PMID: 38740775 Free PMC article. - Unveiling the Mechanisms of EGCG-p53 Interactions through Molecular Dynamics Simulations.
Bahena Culhuac E, Bello M. Bahena Culhuac E, et al. ACS Omega. 2024 Apr 23;9(18):20066-20085. doi: 10.1021/acsomega.3c10523. eCollection 2024 May 7. ACS Omega. 2024. PMID: 38737068 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous