The DOI matches its Crossref record; 78 of the 84 references it cites were found in a registry or an index.
The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites.
Open accessAbstract
Upon DNA damage, the amino terminus of p53 is phosphorylated at a number of serine residues including S20, a site that is particularly important in regulating stability and function of the protein. Because no known kinase has been identified that can modify this site, HeLa nuclear extracts were fractionated and S20 phosphorylation was followed. We discovered that a S20 kinase activity copurifies with the human homolog of the Schizosaccharomyces pombe checkpoint kinase, Chk1 (hCHK1). We confirmed that recombinant hCHK1, but not a kinase-defective version of hCHK1, can phosphorylate p53 in vitro at S20. Additional inducible amino- and carboxy-terminal sites in p53 are also phosphorylated by hCHK1, indicating that this is an unusually versatile protein kinase. It is interesting that hCHK1 strongly prefers tetrameric to monomeric p53 in vitro, consistent with our observation that phosphorylation of amino-terminal sites in vivo requires that p53 be oligomeric. Regulation of the levels and activity of hCHK1 in transfected cells is directly correlated with the levels of p53; expression of either a kinase-defective hCHK1 or antisense hCHK1 leads to reduced levels of cotransfected p53, whereas overexpression of wild-type hCHK1 or the kinase domain of hCHK1 results in increased levels of expressed p53 protein. The human homolog of the second S. pombe checkpoint kinase, Cds1 (CHK2/hCds1), phosphorylates tetrameric p53 but not monomeric p53 in vitro at sites similar to those phosphorylated by hCHK1 kinase, suggesting that both checkpoint kinases can play roles in regulating p53 after DNA damage.
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“and hChk2, in turn, phosphorylates yet another amino-terminal Ser residue (Ser 20) in p53”
From Cell cycle checkpoint signaling through the ATM and ATR kinases (2001) · cites this paper as Shieh et al. 2000
In the citing paper
“These phosphorylation events contribute to disrupting the p53-Mdm2 (Chehab et al., 2000; Shieh et al., 2000), and Mdm2-DAXX (Tang et al., 2013) interactions, as well as to the degradation of Mdm2 and Mdm4 (Stommel and Wahl, 2004; Chen et al., 2005; Pereg et al., 2005, 2006; LeBron et al., 2006).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Shieh et al., 2000
In the citing paper
“p53 is phosphorylated at Ser20 by the checkpoint kinase Chk2 after IR, which results in p53's dissociation from Mdm2 and its subsequent stabilization”
From USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010) · cites this paper as Shieh et al., 2000
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Citations
Cites
p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · cited 1×
“Another p53 target gene, MDM2, encodes a p53-binding protein that negatively regulates the activity (Momand et al. 1992; Oliner et al. 1993) and the stability of p53 (Haupt et al. 1997; Kubbutat et al. 1997; Midgley and Lane 1997).”
BackgroundMomand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113
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DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C. (1997) · Cell · doi:10.1016/s0092-8674(00)80416-x · Cited by 2,100
Self-citationCell Cycle Checkpoints: Preventing an Identity Crisis
Elledge, S. J. (1996) · Science · doi:10.1126/science.274.5293.1664 · Cited by 2,050
Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53
Canman, C. E., Lim, D.-S., Cimprich, K. A., Taya, Y., Tamai, K., Sakaguchi, K., Appella, E., Kastan, M. B., & Siliciano, J. D. (1998) · Science · doi:10.1126/science.281.5383.1677 · Cited by 2,042
Self-citationEnhanced Phosphorylation of p53 by ATM in Response to DNA Damage
Banin, S., Moyal, L., Shieh, S.-Y., Taya, Y., Anderson, C. W., Chessa, L., Smorodinsky, N. I., Prives, C., Reiss, Y., Shiloh, Y., et al. (1998) · Science · doi:10.1126/science.281.5383.1674 · Cited by 1,797
Self-citationOncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,474
Flagged first, then by citations
6 of the 84 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Mayo, 1997, Mdm2 phosphorylation by DNA-dependent protein kinase prevents ineraction with p53., Cancer Res., 57, 5013
Cited by
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Cisplatin: mode of cytotoxic action and molecular basis of resistance
Siddik, Z. H. (2003) · Oncogene · doi:10.1038/sj.onc.1206933 · Cited by 3,335
The DNA damage response: putting checkpoints in perspective
Zhou, B.-B. S., & Elledge, S. J. (2000) · Nature · doi:10.1038/35044005 · Cited by 3,213
Molecular mechanisms of cisplatin resistance
Galluzzi, L., Senovilla, L., Vitale, I., Michels, J., Martins, I., Kepp, O., Castedo, M., & Kroemer, G. (2012) · Oncogene · doi:10.1038/onc.2011.384 · Cited by 2,760
hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase
Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S., Frye, R. A., Pandita, T. K., Guarente, L., & Weinberg, R. A. (2001) · Cell · doi:10.1016/s0092-8674(01)00527-x · Cited by 2,690
Cell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966
Metadata
- Authors
- Shieh, S.-Y., Ahn, J., Tamai, K., Taya, Y., & Prives, C.
- Affiliations
- Seisen University (JP)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-02-01
- Volume
- 14
- Issue
- 3
- Pages
- 289-300
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC316358
- OpenAlex
- W2120921507
- Cited by
- 972
- References
- 84
- Citations by year
- 2026: 11 · 2025: 4 · 2024: 15 · 2023: 22 · 2022: 21 · 2021: 21 · 2020: 28 · 2019: 26 · 2018: 22 · 2017: 19 · 2016: 22 · 2015: 24 · 2014: 39 · 2013: 38 · 2012: 42
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Princess Takamatsu Cancer Research Fund
- National Institutes of Health (CA58316)
- National Cancer Institute (R37CA058316, R01CA058316, CA 58316)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53 phosphorylation, Chk1, Chk2, checkpoint kinase, DNA damage response, p53 oligomerization, p53 stabilization, Schizosaccharomyces pombe, kinase activity
- MeSH terms
- Checkpoint Kinase 1, DNA Damage, HeLa Cells, Humans, Phosphorylation, Protein Kinases, Recombinant Proteins, Blotting, Western, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Schizosaccharomyces pombe Proteins, Checkpoint Kinase 2
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