HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation
Abstract
HER-2/neu amplification or overexpression can make cancer cells resistant to apoptosis and promotes their growth. p53 is crucial in regulating cell growth and apoptosis, and is often mutated or deleted in many types of tumour. Moreover, many tumours with a wild-type gene for p53 do not have normal p53 function, suggesting that some oncogenic signals suppress the function of p53. In this study, we show that HER-2/neu-mediated resistance to DNA-damaging agents requires the activation of Akt, which enhances MDM2-mediated ubiquitination and degradation of p53. Akt physically associates with MDM2 and phosphorylates it at Ser166 and Ser186. Phosphorylation of MDM2 enhances its nuclear localization and its interaction with p300, and inhibits its interaction with p19ARF, thus increasing p53 degradation. Our study indicates that blocking the Akt pathway mediated by HER-2/neu would increase the cytotoxic effect of DNA-damaging drugs in tumour cells with wild-type p53.
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Mdm2 can be phosphorylated by PKB in vitro at Ser166 and Ser186, and this phosphorylation promotes nuclear entry of Mdm2.
“Indeed, it has been reported that Mdm2 could be phosphorylated by PKB in vitro at Ser 166 and Ser 186 , and this phosphorylation promotes the nuclear entry of Mdm2 (31,32).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [32]
The authors failed to detect phosphorylation on Ser186.
“We failed to detect phosphorylation on Ser 186 , which was previously described by other groups (31,32).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [32]
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- Authors
- Zhou, B. P., Liao, Y., Xia, W., Zou, Y., Spohn, B., & Hung, M.-C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Hung, Mien-Chie
- Venue
- Nature Cell Biology
- Published
- 2001-10-08
- Volume
- 3
- Issue
- 11
- Pages
- 973-982
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1500729563
- Cited by
- 951
- References
- 35
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 14 · 2023: 17 · 2022: 26 · 2021: 18 · 2020: 25 · 2019: 22 · 2018: 33 · 2017: 25 · 2016: 34 · 2015: 40 · 2014: 43 · 2013: 48 · 2012: 69
- FWCI
- 22.06
- Type
- journal article
- Language
- en
- Update notices
- erratum (2002-09-01)
- Open access
- closed
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca077858-03)
- National Cancer Institute (CA 78633, CA 83639, R01CA078633, R01CA058880, CA 77858, CA 58880, P50CA083639)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- HER2/neu, p53, MDM2, Akt, p53 ubiquitination, p53 degradation, MDM2 phosphorylation, P300, p19ARF, apoptosis, oncogene signaling
- MeSH terms
- Animals, Cell Line, Transformed, Cell Nucleus, DNA Damage, Etoposide, Humans, Nuclear Proteins, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Ubiquitins, Trans-Activators, Tumor Suppressor Protein p53, 3T3 Cells, Protein Serine-Threonine Kinases, Erb-b2 Receptor Tyrosine Kinases, Nucleic Acid Synthesis Inhibitors, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Protein p14ARF, E1A-Associated p300 Protein, Proto-Oncogene Proteins c-akt, Mice, Proto-Oncogene Proteins c-mdm2
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