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Abstract
Tumor diseases are among the most common causes of death in humans. Our most prolific protection against tumors is provided by the p53 protein, which counteracts the development of
tumors in a variety of ways and is, therefore, called the tumor suppressor gene. A loss of normal p53 function substantially increases the risk for tumor diseases. Tumors that harbor mutations
in the p53 gene and produce a malfunctioning p53 protein usually respond worse to chemotherapy, relapse more often, and thus lead to death faster. Thirty percent of such mutations affect hotspot residues, which leads to a complete loss of transcriptional activity (loss of function, LOF). From the remaining 70% of non-hotspot mutants, over a third retain residual p53 function (partial loss of function, pLOF) and can have a beneficial impact on therapy outcome. Unfortunately, the therapeutic implications of these largely neglected mutants remain unclear.
Within this project, DNA cooperativity mutants p53E177R (p53RR) and p53R178E (p53EE) were used as models for mutations with reduced (p53RR) and almost completely abolished (p53EE) functions of p53. P53RR is unable to induce pro-apoptotic genes but nonetheless is able to perform cell cycle arrest, induce senescence, and initiate DNA repair mechanisms. Both cooperativity mutants are considered to reserve transcription-independent pro-apoptotic functions. In previous experiments, different clinical effects were observed after the therapy of lymphoma in mice involving the p53RR and p53EE mutants. Even though both showed superior survival after treatment compared to p53KO lymphoma, their therapy effectiveness was not the same. Interestingly, p53RR led quickly to a relapse in almost all tested mice and brought only slight survival advantages over p53KO mutants. In contrast, mice with p53EE lymphomas survived significantly longer after therapy, and around 30% of mice enjoyed stable remission. This superior therapeutic response of p53EE lymphomas was unexpected since p53EE is unable to regulate gene expression, while in p53RR mutants, many transcriptional
functions are preserved and were most likely activated during chemotherapy. This led to the assumption that the residual transcriptional functions of p53RR could, in this context, be
counterproductive and impair therapy efficiency.
To pursue this question, we analyzed the functional and expressional features of the different p53 genotypes under stressed and unstressed conditions. To assess the influence of the residual
canonical p53 functions of p53RR in mice, a list of genes has been selected, comprising either direct p53 targets or those closely associated with p53-mediated pathways. Utilizing the
CRISPR/Cas9 system, knockout p53RR lymphoma cell lines lacking these genes were generated and introduced in further in vivo experiments.
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Dates
Issued: 2025-09-23
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Has part: Klimovich, B., Meyer, L., Merle, N., Neumann, M., König, A. M., Ananikidis, N., Keber, C. U., Elmshäuser, S., Timofeev, O., & Stiewe, T. (2022). Partial p53 reactivation is sufficient to induce cancer regression. Journal of Experimental and Clinical Cancer Research, 41(1). https://doi.org/10.1186/s13046-022-02269-6
Faculty
FB20:Medizin
Language
en
Keywords
p53cooperativity mutationlymphomaapoptosisimmune systemdna bindingp53RR
DFG-subjects
205-14 Hämatologie, Onkologie204-05 Immunologie201-05 Allgemeine Genetik und funktionelle Genomforschung
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Ananikidis, Nikolaos: p53RR in the therapy of Eμ-Myc lymphoma. : 2025-09-23.
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Except where otherwised noted, this item's license is described as Attribution 4.0 International