Mechanisms of p53-dependent apoptosis
Abstract
Cellular stresses, such as growth factor deprivation, DNA damage or oncogene expression, lead to stabilization and activation of the p53 tumour suppressor protein. Depending on the cellular context, this results in one of two different outcomes: cell cycle arrest or apoptotic cell death. Cell death induced through the p53 pathway is executed by the caspase proteinases, which, by cleaving their substrates, lead to the characteristic apoptotic phenotype. Caspase activation by p53 occurs through the release of apoptogenic factors from the mitochondria, including cytochrome c and Smac/DIABLO. Released cytochrome c allows the formation of a high-molecular weight complex, the apoptosome, which consists of the adapter protein Apaf-1 and caspase 9, which is activated following recruitment into the apoptosome. Active caspase 9 then cleaves and activates the effector caspases, such as caspases-3 and -7, which execute the death program. Released Smac/DIABLO facilitates caspase activation through repression of the IAP caspase inhibitor proteins. The release of mitochondrial apoptogenic factors is regulated by the pro- and anti-apoptotic Bcl-2 family proteins, which either induce or prevent the permeabilization of the outer mitochondrial membrane. The mechanism by which p53 signals to the Bcl-2 family proteins is unclear. It was shown that some of the pro-apoptotic family members, such as Bax, Noxa or PUMA, are transcriptional targets of p53. In addition, transcription-independent, pro-apoptotic activities of p53 have been described. The elucidation of the p53-dependent pathway, resulting in mitochondrial outer membrane permeabilization through the pro-apoptotic Bcl-2 family proteins, is a key to unveiling the mechanism of stress-induced apoptosis.
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AP-1 and NF-κB are associated with skin dryness, pigmentation, laxity, deep wrinkling, and apoptosis activation.
“These transcription factors are associated with skin dryness, pigmentation, laxity, deep wrinkling [55, 56], and apoptosis activation [57, 58].”
From Antioxidants from Plants Protect against Skin Photoaging (2018) · cites this paper as [58]
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“The p53 protein is concerned in regulating apoptosis, induced by hypoxia through regulation of apoptosis related genes such as PERP, NOXA, PUMA, and Bax (Schuler and Green 2001).”
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“Bax and caspases are key targets in the p53-mediated cell death pathway (for review, see Schuler and Green 2001).”
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“Next, it activates transcription of genes encoding proteins involved in cell cycle control, including p21, and thus prevents transition to S phase (Fig. 1 )[ 3]. Alternatively, p53 can turn on expression of pro-apoptotic genes and induce apoptosis [ 4 ].”
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BackgroundRegulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis
Leech, M. T., Lacey, D. C., Xue, J. R., Santos, L. L., Hutchinson, P. E., Wolvetang, E. J., David, J. R., Bucala, R., & Morand, E. F. (2003) · Arthritis & Rheumatism · doi:10.1002/art.11165 · Cited by 114 · see citing works
Lim, D. Y., & Park, J. H. Y. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90490.2008 · Cited by 111 · see citing works
“6, B and C). p53 is known to induce apoptosis via the transcriptional stimulation of a variety of apoptosis-inducing genes, including Bax, Bid, DR5, Fax, Noxa, and PUMA (29, 37).”
BackgroundHypoxia-inducible factors and hypoxic cell death in tumour physiology
Bacon, A., & Harris, A. L. (2004) · Annals of Medicine · doi:10.1080/07853890410018231 · Cited by 112 · see citing works
Seo, H., Choi, H., Kim, S.-R., et al. (2012) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-012-1310-2 · Cited by 110 · see citing works
“p53-dependent apoptosis is produced by the caspase proteinases and related to pro-apoptotic proteins such as BAX, NOXA, and PUMA [43].”
BackgroundHericium erinaceus enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells
Lee, J. S., & Hong, E. K. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.05.006 · Cited by 106 · see citing works
miR‐34c works downstream of p53 leading to dairy goat male germline stem‐cell ( mGSC s) apoptosis
Li, M., Yu, M., Liu, C., et al. (2013) · Cell Proliferation · doi:10.1111/cpr.12013 · Cited by 106 · see citing works
Chao, J. C. (2006) · World Journal of Gastroenterology · doi:10.3748/wjg.v12.i28.4478 · Cited by 106 · see citing works
“. Activation of p53 tumor suppressor protein can lead to cell cycle arrest and apoptosis in response to DNA damage [ 32 ]”
BackgroundTanjoni, I., Weinlich, R., Della-Casa, M. S., Clissa, P. B., Saldanha-Gama, R. F., de Freitas, M. S., Barja-Fidalgo, C., Amarante-Mendes, G. P., & Moura-da-Silva, A. M. (2005) · Apoptosis · doi:10.1007/s10495-005-2945-1 · Cited by 106 · see citing works
Yamada, T., Goto, M., Punj, V., Zaborina, O. E., Kimbara, K., Gupta, T. K. D., & Chakrabarty, A. M. (2002) · Infection and Immunity · doi:10.1128/iai.70.12.7054-7062.2002 · Cited by 103 · see citing works
“Since p53 is a known inducer of apoptosis (2, 31, 40), these observations indicated that p53 might play a role in the induction of apoptosis by azurin-cytochrome c551.”
BackgroundInfluentialBH3-mimetics: recent developments in cancer therapy
Townsend, P. A., Kozhevnikova, M. V., Cexus, O., Zamyatnin, A. A., & Soond, S. M. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02157-5 · Cited by 101 · see citing works
“Like NOXA [36] and PUMA [37, 38], Smac/DIABLO [39] is also resident on the cytoplasmic face of the MOM, and which uniquely allows it to fulfill its role as a positive activator of caspases, through it binding and inhibiting the Inhibitor of Apoptosis Proteins (IAPs), from the extrinsic and intrinsic arms of the apopto…”
BackgroundWhen one is better than two: RNA with dual functions
Ulveling, D., Francastel, C., & Hubé, F. (2010) · Biochimie · doi:10.1016/j.biochi.2010.11.004 · Cited by 101 · see citing works
“In normal conditions, p53 protein is persistently degraded by the proteasome (for review see [56; 59; 60; 97-99]).”
BackgroundAsbestos-Induced Pulmonary Toxicity: Role of DNA Damage and Apoptosis
Upadhyay, D., & Kamp, D. W. (2003) · Experimental Biology and Medicine · doi:10.1177/153537020322800602 · Cited by 100 · see citing works
Seo, H., Jo, J. K., Ku, J. M., Choi, H., Choi, Y. K., Woo, J. K., Kim, H. I., Kang, S., Lee, K. M., Nam, K. W., et al. (2015) · Bioscience Reports · doi:10.1042/bsr20150165 · Cited by 100 · see citing works
Wang, T., & Morgan, J. I. (2006) · Brain Research · doi:10.1016/j.brainres.2006.07.065 · Cited by 99 · see citing works
Akhter, R., Sanphui, P., & Biswas, S. C. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.519355 · Cited by 99 · see citing works
“The Bcl-2 family comprises pro-survival (e.g. Bcl-2 and BclxL), multidomain proapoptotic (e.g. BAX and BAK), and BH3-only proapoptotic (e.g. Bim (Bcl-2-interacting mediator of cell death), Bid, and Puma) proteins (6).”
BackgroundInfluentialYamada, T., Hiraoka, Y., Ikehata, M., Kimbara, K., Avner, B. S., Das Gupta, T. K., & Chakrabarty, A. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400899101 · Cited by 98 · see citing works
Ceramide Synthase-dependent Ceramide Generation and Programmed Cell Death
Mullen, T. D., Jenkins, R. W., Clarke, C. J., Bielawski, J., Hannun, Y. A., & Obeid, L. M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.230870 · Cited by 99 · see citing works
Pathway of deoxynivalenol-induced apoptosis in human colon carcinoma cells
Bensassi, F., Golli‐Bennour, E. E., Abid‐Essefi, S., et al. (2009) · Toxicology · doi:10.1016/j.tox.2009.07.020 · Cited by 97 · see citing works
A Review of Molecular Mechanisms of the Anti-Leukemic Effects of Phenolic Compounds in Honey
Abubakar, M. B., Abdullah, W. Z., Sulaiman, S. A., & Suen, A. B. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131115054 · Cited by 95 · see citing works
“there are insults to the cells in the form of growth factor deprivation, DNA damage or expression of oncogenes, it will be stimulated and result in either cell cycle arrest or apoptotic cell death [28].”
BackgroundWang, H., Liu, H., Zheng, Z., Zhang, K., Wang, T.-P., Sribastav, S. S., Liu, W., & Liu, T. (2011) · APOPTOSIS · doi:10.1007/s10495-011-0644-7 · Cited by 94 · see citing works
Shangary, S., Ding, K., Qiu, S., Nikolovska-Coleska, Z., Bauer, J. A., Liu, M., Wang, G., Lu, Y., McEachern, D., Bernard, D., et al. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0140 · Cited by 91 · see citing works
“MI-43 Induces Selective Apoptosis in Cancer Cells withWild-type p53 Because p53 is a strong inducer of apoptosis (4) and activation of p53 by MI-43 is observed in both normal and cancer cells, MI-43 could be toxic to both types of cells.”
BackgroundWichmann, A., Jaklevic, B. R., & Su, T. T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510528103 · Cited by 87 · see citing works
Sardão, V. A., Oliveira, P. J., Holy, J. M., et al. (2009) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-009-0932-x · Cited by 91 · see citing works
“that p53 protein can behave as a pro-apoptotic factor when directly translocated to mitochondria [21].”
BackgroundThe molecular mechanisms of oesophageal cancer
McCabe, M., & Dlamini, Z. (2004) · International Immunopharmacology · doi:10.1016/j.intimp.2004.11.017 · Cited by 90 · see citing works
“It is known that tumour suppressor genes, oncogenes, and apoptotic genes are involved in the initiation and development of oesophageal cancer, but to date no gene directly related to oesophageal cancer has been identified [10].”
BackgroundBakhshi, J., Weinstein, L., Poksay, K. S., et al. (2008) · APOPTOSIS · doi:10.1007/s10495-008-0221-x · Cited by 89 · see citing works
Mechanism of apoptosis induced by copper in PC12 cells
Kawakami, M., Inagawa, R., Hosokawa, T., Saito, T., & Kurasaki, M. (2008) · Food and Chemical Toxicology · doi:10.1016/j.fct.2008.02.014 · Cited by 90 · see citing works
“It induces the activation of Bax and suppression of Bcl-2 (Schuler and Green, 2001).”
Background
- Authors
- Schuler, M., & Green, D. R.
- Affiliations
- Department of Medicine III, Johannes Gutenberg University, 55101 Mainz, Germany
- La Jolla Institute for Immunology (US)
- ORCID
- Green, D. R.
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2001-11-01
- Volume
- 29
- Issue
- 6
- Pages
- 684-688
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- OpenAlex
- W2091766574
- Cited by
- 641
- References
- 0
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 15 · 2023: 17 · 2022: 18 · 2021: 13 · 2020: 29 · 2019: 25 · 2018: 22 · 2017: 21 · 2016: 23 · 2015: 22 · 2014: 25 · 2013: 26 · 2012: 38
- FWCI
- 11.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, apoptosis, caspase activation, apoptosome, cytochrome c, Smac/DIABLO, IAP inhibitors, Bcl-2 family proteins, mitochondrial outer membrane permeabilization, Bax, Noxa, PUMA, cell cycle arrest, DNA damage, growth factor deprivation, oncogene expression
- MeSH terms
- Animals, Enzyme Activation, Humans, Mitochondria, Models, Biological, Transcription, Genetic, Tumor Suppressor Protein p53, Apoptosis, Caspases
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