Nutlin-3 Affects Expression and Function of Retinoblastoma Protein
Open accessAbstract
The retinoblastoma protein (Rb) plays a pivotal role in regulating cell proliferation and apoptosis. Nutlin-3, a small molecule MDM2 antagonist blocking interaction between MDM2 and p53, activates p53 resulting in cell growth arrest or apoptosis in various cancer cells. However, the molecular basis for the different cellular responses upon nutlin-3 treatment is not fully understood. In this study, we show that nutlin-3 activates p53 resulting in a dramatic increase in MDM2 expression and a marked reduction in total Rb protein levels. Interestingly, nutlin-3 reduces the levels of hypophosphorylated Rb and induces massive apoptosis in SJSA-1 cells, which can be largely rescued by knockdown of MDM2 or by expression of constitutively active Rb. By contrast, nutlin-3 treatment of several human cancer cells, including A549, U2-OS, and HCT116, results in an accumulation of hypophosphorylated Rb and cell cycle arrest but not apoptosis. Furthermore, we show that down-regulation of Rb by nutlin-3 does not lead to E2F1 activation nor does E2F1 play a critical role for nutlin-3-induced apoptosis in SJSA-1 cells. Taken together, these results suggest that Rb plays a critical role in influencing cellular response to activation of p53 pathway by nutlin-3.
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The cytotoxic effects of Nutlin on p53-proficient cells might depend on the ability of MDM2 to degrade the retinoblastoma protein Rb.
“Another previous report argued that the cytotoxic effects of Nutlin on p53-proficient cells might depend on the ability of MDM2 to degrade the retinoblastoma protein Rb27.”
From CDK4 inhibition diminishes p53 activation by MDM2 antagonists (2018) · cites this paper as [27]
In cells where accumulated MDM2 leads to degradation of hypophosphorylated Rb, apoptosis can be induced, but when Rb remains, the cells merely arrest.
“In cells where accumulated MDM2 leads to the degradation of hypophosphorylated Rb, apoptosis can be induced, but when Rb remains, the cells merely arrest.”
From CDK4 inhibition diminishes p53 activation by MDM2 antagonists (2018) · cites this paper as [27]
This would result in decreased apoptosis.
“This, perhaps in addition to the diminished p53 activity reported here, would then result in decreased apoptosis27.”
From CDK4 inhibition diminishes p53 activation by MDM2 antagonists (2018) · cites this paper as [27]
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References 31 · Cited by 33
Research works printed but not linked: 1
- Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., Myklebost, O., Heimbrook, D. C., and Vassilev, L. T. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 1888 -1893
- Authors
- Du, W., Wu, J., Walsh, E. M., Zhang, Y., Chen, C. Y., & Xiao, Z.-X. J.
- Affiliations
- Boston University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Xiao, Zhi-Xiong Jim
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 284
- Issue
- 39
- Pages
- 26315-26321
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2785319
- OpenAlex
- W2074778020
- Cited by
- 33
- References
- 31
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 2 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 1 · 2014: 1 · 2013: 3 · 2012: 2
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA079804, CA79804)
- National Institute of General Medical Sciences (R01GM070017, GM-70017)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- Nutlin-3, retinoblastoma protein, MDM2, p53 activation, apoptosis, cell cycle arrest, E2F1, p53 pathway
- MeSH terms
- Cell Cycle, Cell Line, Flow Cytometry, Humans, Imidazoles, Phosphorylation, Piperazines, Blotting, Western, Signal Transduction, Tumor Suppressor Protein p53, Retinoblastoma Protein, Apoptosis, RNA Interference, HCT116 Cells, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Proto-Oncogene Proteins c-mdm2
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