Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA
Open accessAbstract
Expression of mutant p53 correlates with poor prognosis in many tumors, therefore strategies aimed at reactivation of mutant p53 are likely to provide important benefits for treatment of tumors that are resistant to chemotherapy and radiotherapy. We have previously identified and characterized a small molecule RITA which binds p53 and induces a conformational change which prevents the binding of p53 to several inhibitors, including its own destructor MDM2. In this way, RITA rescues the tumor suppression function of wild type p53. Here, we demonstrate that RITA suppressed the growth and induced apoptosis in human tumor cell lines of a diverse origin carrying mutant p53 proteins. RITA restored transcriptional transactivation and transrepression function of several hot spot p53 mutants. The ability of RITA to rescue the activity of different p53 mutants suggests its generic mechanism of action. Thus, RITA is a promising lead for the development of anti-cancer drugs that reactivate the tumor suppressor function of p53 in cancer cells irrespective whether they express mutant or wild type p53.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The RAJI cell line harbors the loss-of-function mutant alleles R213Q and Y234H.
“The cell line RAJI, which harbors the loss-of-function mutant alleles R213Q and Y234H [34–36] for p53 targets including TLR3 and p21 (Supplementary Figure S4A), was treated with the reactivating drugs RITA [36] and PRIMA-1 [37] as well as with the anticancer drugs doxorubicin (DXR) and 5-fluorouracil (5FU) to induce p53.”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [36]
Table 1, in the section on RITA’s growth suppression, identifies Raji as carrying mutant p53 but lists its mutations as “Arg213, thr234,” not the claimed R213Q and Y234H. The source therefore supports that Raji has p53 mutations at those positions, but gives different amino-acid identities. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredRITA and PRIMA-1 increased the expression of the p53 targets p21 and PUMA in RAJI cells.
“As shown in Figure 5A, RITA and PRIMA-1 increased the expression of the p53 targets p21 and PUMA, based on qPCR measurements at 24 after their addition to cell cultures, similar to previous reports for other p53 mutants [36, 37].”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [36]
The section “Restoration of the transcriptional function of mutant p53 in cells” (page not specified) reports qPCR induction of p21 in SKBR-3 cells and PUMA in A431 cells after RITA treatment, supporting the comparison with other p53 mutants. It does not report that PRIMA-1 induced either target; its PRIMA-1 comparison concerns cell-killing potency. The RAJI result is presented as the citing authors’ own finding, not as a result of this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRITA was found to suppress growth of cancer cell lines carrying various p53 mutations and restored the transcriptional functions of several p53 mutant alleles including R175H, R213Q, Y234H, R248W, R273H and R280K that resulted in induction of apoptosis.
“In particular, RITA was found to suppress growth of cancer cell lines carrying various p53 mutations and restored the transcriptional functions of several p53 mutant alleles including R175H, R213Q, Y234H, R248W, R273H and R280K that resulted in induction of apoptosis [36, 48].”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [36]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
A Chemical Inhibitor of p53 That Protects Mice from the Side Effects of Cancer Therapy
Komarov, P. G., Komarova, E. A., Kondratov, R. V., Christov-Tselkov, K., Coon, J. S., Chernov, M. V., & Gudkov, A. V. (1999) · Science · doi:10.1126/science.285.5434.1733 · Cited by 1,270 · see citing works
Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound
Bykov, V. J. N., Issaeva, N., Shilov, A., Hultcrantz, M., Pugacheva, E., Chumakov, P., Bergman, J., Wiman, K. G., & Selivanova, G. (2002) · Nature Medicine · doi:10.1038/nm0302-282 · Cited by 1,067 · see citing works
Self-citationAwakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881 · see citing works
Modeling the Therapeutic Efficacy of p53 Restoration in Tumors
Martins, C. P., Brown-Swigart, L., & Evan, G. I. (2006) · Cell · doi:10.1016/j.cell.2006.12.007 · Cited by 600 · see citing works
Reactivation of mutant p53: molecular mechanisms and therapeutic potential
Selivanova, G., & Wiman, K. G. (2007) · Oncogene · doi:10.1038/sj.onc.1210295 · Cited by 186 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 15
- Vousden KH, Prives C. Blinded by the Light: The Growing Complexity of p53. Cell 2009; 137:413-31.
- Foster BA, Coffey HA, Morin MJ, Rastinejad F. Pharmacological rescue of mutant p53 conformation and function. Science 1999; 286:2507-10.
- Bykov VJ, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, et al. Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem 2005; 280:30384-91.
- Zache N, Lambert JM, Rokaeus N, Shen J, Hainaut P, Bergman J, et al. Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol Oncol 2008; 2:70-80.
- Weinmann L, Wischhusen J, Demma MJ, Naumann U, Roth P, Dasmahapatra B, et al. A novel p53 rescue compound induces p53-dependent growth arrest and sensitises glioma cells to Apo2L/TRAIL-induced apop- tosis. Cell Death Differ 2008; 15:718-29.
- Kravchenko JE, Ilyinskaya GV, Komarov PG, Agapova LS, Kochetkov DV, Strom E, et al. Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. Proc Natl Acad Sci USA 2008; 105:6302-7.
- Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR. Targeted rescue of a destabi- lized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci USA 2008; 105:10360-5.
- Wang W, Takimoto R, Rastinejad F, El-Deiry WS. Stabilization of p53 by CP-31398 inhibits ubiquitina- tion without altering phosphorylation at serine 15 or 20 or MDM2 binding. Mol Cell Biol 2003; 23:2171-81.
- Liu WL, Midgley C, Stephen C, Saville M, Lane DP. Biological significance of a small highly conserved region in the N terminus of the p53 tumour suppressor protein. J Mol Biol 2001; 313:711-31.
- Okorokov AL, Sherman MB, Plisson C, Grinkevich V, Sigmundsson K, Selivanova G, et al. The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity. EMBO J 2006; 25:5191-200.
- Wiman KG, Magnusson KP, Ramqvist T, Klein G. Mutant p53 detected in a majority of Burkitt lym- phoma cell lines by monoclonal antibody PAb240. Oncogene 1991; 6:1633-9.
- Issaeva N, Friedler A, Bozko P, Wiman KG, Fersht AR, Selivanova G. Rescue of mutants of the tumor suppres- sor p53 in cancer cells by a designed peptide. Proc Natl Acad Sci USA 2003; 100:13303-7.
- Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 2004; 10:1321-8.
- Strom E, Sathe S, Komarov PG, Chernova OB, Pavlovska I, Shyshynova I, et al. Small-molecule inhibi- tor of p53 binding to mitochondria protects mice from gamma radiation. Nat Chem Biol 2006; 2:474-9.
- Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 2009; 9:701-13.
Cited by
Sorted by citations
Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells
Menendez, D., Lowe, J. M., Snipe, J., & Resnick, M. A. (2016) · Oncotarget · doi:10.18632/oncotarget.11210 · Cited by 31 · see citing works
- Authors
- Zhao, C. Y., Grinkevich, V., Nikulenkov, F., Bao, W., & Selivanova, G.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Bao, Wenjie
- Selivanova, Galina
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2010-05
- Volume
- 9
- Issue
- 9
- Pages
- 1847-1855
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2086042427
- Cited by
- 79
- References
- 6
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 10 · 2016: 5 · 2015: 4 · 2014: 10 · 2013: 5 · 2012: 12
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Cancerfonden
- Vetenskapsrådet
- 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 › Heat shock proteins research
- Keywords
- RITA, mutant p53, p53 reactivation, small molecule p53 activators, apoptosis, transcriptional activation, transrepression, tumor suppression, cancer chemotherapy resistance, radiotherapy resistance, anticancer drug development
- MeSH terms
- Furans, Humans, Mutation, Neoplasms, Protein Binding, Transcriptional Activation, Tumor Suppressor Protein p53, Apoptosis, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
