Journal articles: 'Mutant p53 gain of function'

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Stein, Yan, Varda Rotter, and Ronit Aloni-Grinstein. "Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis." International Journal of Molecular Sciences 20, no. 24 (December 8, 2019): 6197. http://dx.doi.org/10.3390/ijms20246197.

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The p53 protein is mutated in about 50% of human cancers. Aside from losing the tumor-suppressive functions of the wild-type form, mutant p53 proteins often acquire inherent, novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function (GOF). A growing body of evidence suggests that these pro-oncogenic functions of mutant p53 proteins are mediated by affecting the transcription of various genes, as well as by protein–protein interactions with transcription factors and other effectors. In the current review, we discuss the various GOF effects of mutant p53, and how it may serve as a central node in a network of genes and proteins, which, altogether, promote the tumorigenic process. Finally, we discuss mechanisms by which “Mother Nature” tries to abrogate the pro-oncogenic functions of mutant p53. Thus, we suggest that targeting mutant p53, via its reactivation to the wild-type form, may serve as a promising therapeutic strategy for many cancers that harbor mutant p53. Not only will this strategy abrogate mutant p53 GOF, but it will also restore WT p53 tumor-suppressive functions.

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Hall, Callum, and Patricia A. J. Muller. "The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer." International Journal of Molecular Sciences 20, no. 24 (December 7, 2019): 6188. http://dx.doi.org/10.3390/ijms20246188.

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The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of p53 as a tumour suppressor has been thoroughly investigated, but the functions of all isoforms and mutants and the interplay between them are still poorly understood. Mutant p53 proteins lose p53 function, display dominant-negative (DN) activity and display gain-of-function (GOF) to varying degrees. GOF was originally attributed to mutant p53′s inhibitory function over the p53 family members p63 and p73. It has become apparent that this is not the only way in which mutant p53 operates as a large number of transcription factors that are not related to p53 are activated on mutant p53 binding. This raises the question to what extent mutant p53 binding to p63 and p73 plays a role in mutant p53 GOF. In this review, we discuss the literature around the interaction between mutant p53 and family members, including other binding partners, the functional consequences and potential therapeutics.

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Chen, Sisi, Hao Yu, Michihiro Kobayashi, Rui Gao, H. Scott Boswell, and Yan Liu. "Gain-of-Function Mutant p53 Enhances Hematopoietic Stem Cell Self-Renewal." Blood 124, no. 21 (December 6, 2014): 260. http://dx.doi.org/10.1182/blood.v124.21.260.260.

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Abstract The tumor suppressor p53 is a critical regulator of hematopoietic stem cell (HSC) behavior and we demonstrated that p53 maintains HSC quiescence and regulates HSC response to irradiation (Liu et al., Cell Stem Cell, 2009).While TP53 mutations are less common in acute myeloid leukemia (5 to 8%) than in solid tumors (50%), they are associated with poor prognosis and abnormal cytogenetics, especially abnormalities in chromosomes 5 and 7. These mutations may abolish some but not necessarily all of the functions of p53 in regulating stem cell behavior. Therefore, this aspect of p53 function needs further investigation. To define the role of mutant p53 in the pathogenesis of AML, we introduced 9 hot-spot p53 mutants identified in AML patients, including p53R248W, p53R273H and p53Y220C, into wild type hematopoietic cells using retrovirus-mediated transduction and investigated the role of these p53 mutants in regulating HSC self-renewal. We found that hematopoietic cells expressing p53R248W, p53Y220C or p53R273H show enhanced repopulating potential 16 weeks following transplantation. As codon 248 of the p53 protein is most frequently mutated in AML, we decided to investigate the role of p53R248W mutant in HSCs by using the humanized knock-in mice of p53R248W. In p53 knockout mice, there is a dramatic increase of HSCs (CD48-CD150+Lin-Sca1+c-Kit+ cells); however,we found thatboth wild type andp53R248W mice have similar number of HSCs. While wild type p53 maintains HSC quiescence, expression of p53R248W in HSCs (CD48-CD150+LSKs) does not affect their quiescent state. Asp53R248W does not appear to affect HSC frequency and quiescence, it is not a loss-of-function mutant. We also used bone marrow cells isolated from both wild type and p53R248W mice to perform the serial replating assays and found that expressing p53R248W from the endogenous Trp53 promoter enhances the replating potential of hematopoietic cells. Moreover, we performed serial bone marrow repopulation (BMT) assays and found that the repopulating ability of p53R248W cells was significantly higher than that of the wild type cells in both primary and secondary BMT assays, demonstrating that the p53R248W mutant enhances HSC self-renewal in vivo. Furthermore, we observed that HSCs expressing p53R248W are resistant to genotoxic stress induced by irradiation and the p53R248W mice show extended survival following sub-lethal dose of total body irradiation. Ample data indicate that mutant p53 proteins not only lose their tumor suppressive functions, but also gain new abilities that promote tumorigenesis. To understand how mutant p53 enhances HSC self-renewal, we performed gene expression profiling assays by using HSCs isolated from wild type and p53R248W mice. We also utilized Ingenuity Pathway analysis software to group putative mutant p53 target genes into different pathways. While we did not observe change in the expression of p53 target genes in p53R248W HSCs, several pathways that are important for leukemogenesis, including epigenetic and DNA damage repair pathways, are altered in HSCs expressing p53R248W, demonstrating that p53R248W is a gain-of-function mutant. Given that TP53 mutations are correlated with poor prognosis, pharmacological inhibition of mutant p53 may be a promising therapeutic strategy for AML patients with TP53 mutations. Small molecule PRIMA-1 has been shown to restore wild-type conformation to some mutant p53 proteins and induce apoptosis in human tumor cells. We found that hematopoietic cells expressing mutant p53 are sensitive to PRIMA-1 treatment and undergo p53-dependent apoptosis. Furthermore, we observed that PRIMA-1 inhibits the growth of primary human AML cells with TP53 mutation in a dosage-dependent manner. Taken together, we demonstrated that gain-of-function mutant p53 enhances hematopoietic stem cell self-renewal through regulating epigenetic and DNA damage repair pathways. Our data also suggest that pharmacological inhibition of mutant p53 may sensitize the drug-resistant leukemia stem cells (LSCs) to chemotherapy and improves leukemia treatment. Disclosures No relevant conflicts of interest to declare.

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Chiang, Yen-Ting, Yi-Chung Chien, Yu-Heng Lin, Hui-Hsuan Wu, Dung-Fang Lee, and Yung-Luen Yu. "The Function of the Mutant p53-R175H in Cancer." Cancers 13, no. 16 (August 13, 2021): 4088. http://dx.doi.org/10.3390/cancers13164088.

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Wild-type p53 is known as “the guardian of the genome” because of its function of inducing DNA repair, cell-cycle arrest, and apoptosis, preventing the accumulation of gene mutations. TP53 is highly mutated in cancer cells and most TP53 hotspot mutations are missense mutations. Mutant p53 proteins, encoded by these hotspot mutations, lose canonical wild-type p53 functions and gain functions that promote cancer development, including promoting cancer cell proliferation, migration, invasion, initiation, metabolic reprogramming, angiogenesis, and conferring drug resistance to cancer cells. Among these hotspot mutations, p53-R175H has the highest occurrence. Although losing the transactivating function of the wild-type p53 and prone to aggregation, p53-R175H gains oncogenic functions by interacting with many proteins. In this review, we summarize the gain of functions of p53-R175H in different cancer types, the interacting proteins of p53-R175H, and the downstream signaling pathways affected by p53-R175H to depict a comprehensive role of p53-R175H in cancer development. We also summarize treatments that target p53-R175H, including reactivating p53-R175H with small molecules that can bind to p53-R175H and alter it into a wild-type-like structure, promoting the degradation of p53-R175H by targeting heat-shock proteins that maintain the stability of p53-R175H, and developing immunotherapies that target the p53-R175H–HLA complex presented by tumor cells.

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Oren, M., and V. Rotter. "Mutant p53 Gain-of-Function in Cancer." Cold Spring Harbor Perspectives in Biology 2, no. 2 (December 16, 2009): a001107. http://dx.doi.org/10.1101/cshperspect.a001107.

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Aschauer, Lydia, and Patricia A. J. Muller. "Novel targets and interaction partners of mutant p53 Gain-Of-Function." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 460–66. http://dx.doi.org/10.1042/bst20150261.

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In many human cancers p53 expression is lost or a mutant p53 protein is expressed. Over the past 15 years it has become apparent that a large number of these mutant p53 proteins have lost wild type function, but more importantly have gained functions that promote tumorigenesis and drive chemo-resistance, invasion and metastasis. Many researchers have investigated the underlying mechanisms of these Gain-Of-Functions (GOFs) and it has become apparent that many of these functions are the result of mutant p53 hijacking other transcription factors. In this review, we summarize the latest research on p53 GOF and categorize these in light of the hallmarks of cancer as presented by Hannahan and Weinberg.

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Zhang, Yanhong, Wensheng Yan, and Xinbin Chen. "Mutant p53 Disrupts MCF-10A Cell Polarity in Three-dimensional Culture via Epithelial-to-mesenchymal Transitions." Journal of Biological Chemistry 286, no. 18 (March 22, 2011): 16218–28. http://dx.doi.org/10.1074/jbc.m110.214585.

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Mutant p53 is not only deficient in tumor suppression but also acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knock-in mice that carry one null allele and one mutant allele of the p53 gene. These knock-in mice develop aggressive tumors compared with p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for cell survival and resistance to DNA damage. To further define mutant p53 gain of function, we used the MCF-10A three-dimensional model of mammary morphogenesis. MCF-10A cells in three-dimensional culture undergo a series of morphological changes and form polarized and growth-arrested spheroids with hollow lumen, which resembles normal glandular architectures in vivo. Here, we found that endogenous wild-type p53 in MCF-10A cells was not required for acinus formation, but knockdown of endogenous wild-type p53 (p53-KD) led to partial clearance of cells in the lumen due to decreased apoptosis. Consistent with this, p53-KD altered expression patterns of the cell adhesion molecule E-cadherin, the cytoskeletal marker β-catenin, and the extracellular matrix protein laminin V. We also found that ectopic expression of the mutant G245S led to a phenotype similar to p53-KD, whereas a combination of ectopic expression of siRNA-resistant G245S with p53-KD led to a less cleared lumen. In contrast, ectopic expression of mutant R248W, R175H, and R273H disrupted normal acinus architectures with filled lumen and led to formation of irregular and multiacinus structures regardless of p53-KD. In addition, these mutants altered normal expression patterns and/or levels of E-cadherin, β-catenin, laminin V, and tight junction marker ZO-1. Furthermore, epithelial-to-mesenchymal transitions (EMT) markers, Snail, Slug, and Twist, were highly induced by mutant p53 and/or p53-KD. Together, we postulate that EMT represents a mutant p53 gain of function and mutant p53 alters cell polarity via EMT.

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Zhang, Cen, Juan Liu, Dandan Xu, Tianliang Zhang, Wenwei Hu, and Zhaohui Feng. "Gain-of-function mutant p53 in cancer progression and therapy." Journal of Molecular Cell Biology 12, no. 9 (July 28, 2020): 674–87. http://dx.doi.org/10.1093/jmcb/mjaa040.

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Abstract p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.

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Cai, Bi-He, Zhi-Yu Bai, Ching-Feng Lien, Si-Jie Yu, Rui-Yu Lu, Ming-Han Wu, Wei-Chen Wu, Chia-Chi Chen, and Yi-Chiang Hsu. "NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner." Biomolecules 12, no. 3 (March 12, 2022): 438. http://dx.doi.org/10.3390/biom12030438.

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The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.

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Zhang, Ying, Feng Yuan, Cassandra Grello, Brian Reon, Myron Gibert, Collin Dube, Anindya Dutta, Eric Holland, and Roger Abounader. "CSIG-07. GAIN-OF-FUNCTION MUTANT P53 REGULATES LONG-NONCODING RNAS IN GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii39—vii40. http://dx.doi.org/10.1093/neuonc/noac209.156.

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Abstract P53 is frequently mutated in most human cancers, including glioblastoma (GBM). Many p53 mutants acquire gain-of-function oncogenic effects through only partially understood mechanisms. To investigate the role of gain-of-function mutant p53 (MUT-p53) in GBM, we performed ChIP-seq of wildtype p53 (WT-p53) and MUT-p53 GBM cell lines. Among 2834 unique peaks reads in MUT-p53 cells, we found 242 long non-coding RNAs (lncRNAs) with up to 145 fold enrichment relative to WT-p53. LncRNAs regulate many molecular and cellular functions, including gene expression, cell proliferation, death, cancer stem cell renewal and differentiation. We selected lncRNAs SOX21-AS1 and LINC00643 with highly enriched binding by MUT-p53 and investigated their expressions and functions in the p53 pathway. We performed ChIP confirmation of MUT-p53 binding to the promoters of these lncRNAs. We found that these lncRNAs are deregulated in GBM and correlated with GBM patient survival in the TCGA database. To investigate the functions of these LncRNAs, we knocked down their expressions by siRNA, and found significant cell death induced by si-SOX21-AS1, but not by si-LINC00643. Overexpression of LINC00643 in GBM cells led to inhibition of GBM cell proliferation, migration, invasion and in vivo xenograft growth. LINC00643 mediated the effects of MUT-p53. Co-expression of human LINC00643 and its mouse homologous in a RCAS transgenic mouse model of GBM reduced tumor growth and improved animal survival. To elucidate the mechanisms of action of the lncRNA, we performed Chromatin Isolation by RNA purification high-throughput sequencing (CHIRP-seq) to identify its binding targets. We found that LINC00643 binds to HIF1a 5’ promoter/enhancer region. Overexpression of LINC00643 in GBM cells at hypoxia growth condition reduced HIF1a mRNA and protein expression. Our study shows for the first time that gain-of-function mutant p53 regulates a subset of lncRNAs and that the lncRNAs mediate the oncogenic effects of the MUT-p53 in GBM.

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Bargonetti, Jill, and Carol Prives. "Gain-of-function mutant p53: history and speculation." Journal of Molecular Cell Biology 11, no. 7 (July 2019): 605–9. http://dx.doi.org/10.1093/jmcb/mjz067.

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Stindt, M., P. Muller, and K. H. Vousden. "151 Mutant P53 Gain of Function Via P63." European Journal of Cancer 48 (July 2012): S36—S37. http://dx.doi.org/10.1016/s0959-8049(12)70851-1.

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Barta, Julie A., Kristen Pauley, Andrew V. Kossenkov, and Steven B. McMahon. "The lung-enriched p53 mutants V157F and R158L/P regulate a gain of function transcriptome in lung cancer." Carcinogenesis 41, no. 1 (May 8, 2019): 67–77. http://dx.doi.org/10.1093/carcin/bgz087.

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Abstract Lung cancer is the leading cause of cancer-related deaths in the USA, and alterations in the tumor suppressor gene TP53 are the most frequent somatic mutation among all histologic subtypes of lung cancer. Mutations in TP53 frequently result in a protein that exhibits not only loss of tumor suppressor capability but also oncogenic gain-of-function (GOF). The canonical p53 hotspot mutants R175H and R273H, for example, confer upon tumors a metastatic phenotype in murine models of mutant p53. To the best of our knowledge, GOF phenotypes of the less often studied V157, R158 and A159 mutants—which occur with higher frequency in lung cancer compared with other solid tumors—have not been defined. In this study, we aimed to define whether the lung mutants are simply equivalent to full loss of the p53 locus, or whether they additionally acquire the ability to drive new downstream effector pathways. Using a publicly available human lung cancer dataset, we characterized patients with V157, R158 and A159 p53 mutations. In addition, we show here that cell lines with mutant p53-V157F, p53-R158L and p53-R158P exhibit a loss of expression of canonical wild-type p53 target genes. Furthermore, these lung-enriched p53 mutants regulate genes not previously linked to p53 function including PLAU. Paradoxically, mutant p53 represses genes associated with increased cell viability, migration and invasion. These findings collectively represent the first demonstration that lung-enriched p53 mutations at V157 and R158 regulate a novel transcriptome in human lung cancer cells and may confer de novo function.

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Zhao, Y., C. Zhang, X. Yue, X. Li, J. Liu, H. Yu, V. A. Belyi, Q. Yang, Z. Feng, and W. Hu. "Pontin, a new mutant p53-binding protein, promotes gain-of-function of mutant p53." Cell Death & Differentiation 22, no. 11 (April 10, 2015): 1824–36. http://dx.doi.org/10.1038/cdd.2015.33.

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Zhao, Yuhan, Xuetian Yue, and Wenwei Hu. "Pontin, a novel interactor of mutant p53 that promotes mutant p53 gain of function." Molecular & Cellular Oncology 3, no. 2 (July 29, 2015): e1076587. http://dx.doi.org/10.1080/23723556.2015.1076587.

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Aubrey, Brandon James, Andreas Strasser, Gemma Kelly, Lin Tai, and Marco Herold. "Evidence for Mutant p53 Gain-of-Function Effects in Normal Haemopoietic Cells and Myc-Driven Lymphoma." Blood 124, no. 21 (December 6, 2014): 3589. http://dx.doi.org/10.1182/blood.v124.21.3589.3589.

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Abstract Deregulated c-MYC expression and mutations in p53 are among the most common changes detected in human cancer. It is now established that mutant p53 proteins confer a poor prognosis in human cancer through both loss of wild-type p53 activity as well as various proposed gain-of-function properties. The specific role of mutant p53 in MYC-driven tumorigenesis is not known. The Eμ-Myc mouse model carries a c-Myc transgene under the control of the immunoglobulin heavy chain gene enhancer (Eμ), recapitulating the chromosomal translocation underlying human Burkitt Lymphoma (BL). These mice develop aggressive pre-B or B cell lymphomas and ~20% of those tumours exhibit p53 mutations. We have shown that MYC-driven lymphomas are exquisitely dependent on the pro-survival BCL-2 family member MCL-1 such that loss of a single allele of Mcl-1 leads to dramatic tumour regression and prolonged animal survival. Interestingly, we found that this dependency on MCL-1 is reduced, but not completely ablated, by the presence of a p53 mutation. This suggests an important role for mutant p53 in the sustained survival of MYC-driven lymphomas. We are investigating the effects of five different mutant mouse p53 proteins (V170M, I192S, G280, R246Q, R270H) on tumour initiation, sustained growth and chemoresistance in the Eμ-Myc mouse model. We are further examining the effect of p53 mutations on MCL-1 dependence by using a floxed Mcl-1 gene and a tamoxifen-inducible Cre-recombinase in established Eμ-Myc lymphomas. Preliminary data suggest that both loss of wild-type p53 function as well as retroviral over-expression of mutant p53 can compensate for reduced levels of MCL-1 (loss of one Mcl-1 allele). The underlying mechanisms for this are under investigation. The role of mutant p53 in lymphoma cell survival has been further examined in Eμ-Myc lymphoma-derived cell lines. Enforced over-expression of mutant p53 in cell lines containing wild-type p53 impaired induction of apoptosis by Nutlin3A, an inhibitor of Mdm-2 (the major negative regulator of p53). Remarkably, Nutlin-3a-induced apoptosis was impaired although it caused substantial transcriptional induction of the p53 apoptosis effectors, Puma and Noxa. Importantly, different mutant p53 proteins conferred different levels of protection against cell death. The observed protection against cell death may be partly due to dominant-negative effects of mutant p53, however, it does not appear to be robust enough to account for the extent of cell survival. Furthermore, mutant p53 conferred resistance to docetaxol, which is thought to induce cell death through predominantly p53-independent mechanisms. These data suggest that mutant p53 can protect against both p53-dependent and p53-independent cell death processes. Conversely, transcriptional induction of Noxa and Puma implies that “p53-restoration therapy” may remain a feasible treatment strategy even in tumours that bear mutations in p53 and that the role of a dominant-negative effect for some mutant p53 proteins may be less important than previously considered, at least in lymphoma cells. We are also examining the effect of mutant p53 on lymphoma development utilizing a hematopoietic reconstitution model and retroviral over-expression of mutant p53 proteins. The different mutant p53 proteins investigated exhibited distinct effects during tumorigenesis. The R246Q mutant p53 protein markedly accelerated lymphoma development in the context of MYC over-expression. The R246Q mutant p53 protein demonstrated strong selection in p53-deficient (p53-/-) hematopoietic cells during reconstitution indicative of an advantageous activity in emergency hematopoiesis. Overall, these findings provide evidence for a positive oncogenic role of mutant p53 in hematopoietic cells that provides a particularly potent selective advantage in the context of MYC driven lymphoma development. Importantly, different p53 mutations exhibit different functional properties such that different p53 mutations are likely to be associated with distinct risk in human malignant disease. Disclosures No relevant conflicts of interest to declare.

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Rockwell, Nathan, Max Staller, Maria Cannella, Barak Cohen, and Joshua Rubin. "GENE-59. NOT ALL p53 MUTATIONS ARE CREATED EQUAL: A MURINE ASTROCYTE MODEL FOR HIGH-THROUGHPUT FUNCTIONAL ASSESSMENT OF p53 MISSENSE MUTATIONS." Neuro-Oncology 21, Supplement_6 (November 2019): vi110. http://dx.doi.org/10.1093/neuonc/noz175.461.

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Abstract The tumor suppressor TP53 (p53) is the most commonly mutated gene in cancer and among the most frequently mutated genes in glioblastoma (GBM). The majority of p53 mutations in GBM are missense mutations in the DNA binding domain that lead to the production of full length mutant p53 protein. In addition to the complete loss of tumor suppressor function, these mutations have gain-of-function (GOF) properties either through attenuation of wild-type function or neomorphic functions. The variability in GOF mutations results in heterogeneity in cancer phenotypes between mutants that remain poorly understood. Here, we developed a murine astrocyte model to functionally assess a library of p53 mutants in parallel. Primary astrocytes were isolated from postnatal day one pups possessing a single copy of wild-type p53 flanked by loxP sites (TRP53f/-). We then built a library of 17 individual alleles of recurring mutations in GBM with flanking loxP sites. When co-transfected into the mouse astrocytes with a plasmid expressing Cre recombinase, the endogenous WT p53 was excised and replaced with a single copy of the mutant allele. In this way, all astrocytes expressed a single copy of mutant p53 from the endogenous p53 locus. As the mutant p53 cells expanded, aliquots of cells were extracted for targeted genomic sequencing of the p53 allele. Comparing the allelic frequencies of each mutant overtime revealed a wide distribution of growth rates between mutants. To validate the screen results, wildtype astrocytes were transduced with mutant p53-IRES-eGFP retrovirus to overexpress one of three mutations with divergent growth phenotypes. As observed in the initial screen, equivalent overexpression of the different p53 mutants was sufficient to induce significant differences in growth phenotype, with astrocytes expressing the Y217C growing the fastest, R172H second, and Y202C growing the slowest. Ongoing studies are evaluating mutation-specific p53 binding partners and transcriptional outputs.

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Lakoduk, Ashley M., Cheng-Fan Lee, and Ping-Hung Chen. "Gain-of-“endocytic’ function in mutant p53 cancer cells." International Journal of Biochemistry & Cell Biology 131 (February 2021): 105905. http://dx.doi.org/10.1016/j.biocel.2020.105905.

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Peart, Melissa J., and Carol Prives. "Mutant p53 gain of function: The NF-Y connection." Cancer Cell 10, no. 3 (September 2006): 173–74. http://dx.doi.org/10.1016/j.ccr.2006.08.014.

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Strano, Sabrina, Stefania Dell'Orso, Adriana Maria Mongiovi, Olimpia Monti, Eleonora Lapi, Silvia Di Agostino, Giulia Fontemaggi, and Giovanni Blandino. "Mutant p53 proteins: Between loss and gain of function." Head & Neck 29, no. 5 (2007): 488–96. http://dx.doi.org/10.1002/hed.20531.

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Wang, Jieqiong. "Abstract 1035: VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1035. http://dx.doi.org/10.1158/1538-7445.am2022-1035.

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Abstract Pancreatic cancer is the most lethal malignant neoplasms across the world with the lowest overall five-year survival rate (9%). TP53 is mutated in ~70% of pancreatic ductal adenocarcinomas (PDACs). Hotspot p53 mutants promote cancer cell proliferation, metastasis and metabolism through their gain-of-function (GOF). Among the p53 “hotspot” mutations, R273 is the most frequent mutation position (~12%) with R273H as the most commonly mutated codon (~8%) in PDACs. However, the mechanisms underlying regulation of mutant p53s’ GOF in PDACs remain incompletely understood. In our attempt to address this question, we recently identified the ATPase valosin-containing protein (VCP)/p97 as a novel mutant p53-binding protein by performing immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) analysis. VCP bound to p53-R273H via the DNA-binding domain. VCP inhibition either by genetic depletion or pharmacological inhibition by CB-5083 resulted in the increase of MDM2-mediated ubiquitination and degradation of p53-R273H. VCP did so by binding to MDM2 and disturbing its interaction with mutant p53. As a result, VCP protected mutant p53 from degradation and enhanced its GOF in cancer development. Ablation of VCP retarded PDAC cell growth in vitro and in vivo. Our further studies also unveiled the negative regulation of wt p53 by VCP in cancer cells. Together, these results demonstrate that VCP can strengthen mutant p53’s oncogenic function by stabilizing it and negating wt p53 function, suggesting VCP as a resistant factor for chemotherapy against PDACs and thus a potential therapeutic target of the mutant p53-harboring pancreatic cancers as well as of the wt p53-containing cancer cells. Citation Format: Jieqiong Wang. VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1035.

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Xiong, Shunbin, Dhruv Chachad, Yun Zhang, Jovanka Gencel-Augusto, Mario Sirito, Vinod Pant, Peirong Yang, Chang Sun, and Guillermina Lozano. "Abstract A042: Differences in gain-of-function and inhibitory effects amongst p53 mutants in vivo." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A042. http://dx.doi.org/10.1158/1538-7445.metastasis22-a042.

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Abstract The majority of p53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li-Fraumeni syndrome, contribute to tumorigenesis in vivo, we generated a novel germline p53R245W allele (contact mutation) and compared it to existing p53R172H (structural mutation) and p53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed all three hot-spot mutations exhibited similar inhibitory effects on wild type p53 transcription in vivo and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of p53R245W/+ and p53R270H/+ mice, but not p53R172H/+ mice, was significantly shorter than that of p53+/- mice, demonstrating p53 mutation-specific GOF contributions to tumor development. Furthermore, p53R245W/+ and p53R270H/+ mice had more osteosarcoma metastases than p53R172H/+ mice, indicating that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Omics analyses using RNA-sequencing data from p53R172H/+, p53R245W/+, and p53R270H/+ primary osteosarcomas in comparison to p53+/- indicated GOF was mediated by distinct pathways among the three mutations. Thus, both the inhibitory effect of mutant over WT p53, and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant-specific pathways may be important for therapeutic outcomes in osteosarcomas. Citation Format: Shunbin Xiong, Dhruv Chachad, Yun Zhang, Jovanka Gencel-Augusto, Mario Sirito, Vinod Pant, Peirong Yang, Chang Sun, Guillermina Lozano. Differences in gain-of-function and inhibitory effects amongst p53 mutants in vivo [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A042.

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Vikhanskaya, F., M. K. Lee, M. Mazzoletti, M. Broggini, and K. Sabapathy. "Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gain of function of mutant p53." Nucleic Acids Research 35, no. 6 (March 1, 2007): 2093–104. http://dx.doi.org/10.1093/nar/gkm099.

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Hann, Byron, and Allan Balmain. "Replication of an E1B 55-Kilodalton Protein-Deficient Adenovirus (ONYX-015) Is Restored by Gain-of-Function Rather than Loss-of-Function p53 Mutants." Journal of Virology 77, no. 21 (November 1, 2003): 11588–95. http://dx.doi.org/10.1128/jvi.77.21.11588-11595.2003.

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ABSTRACT ONYX-015 (dl1520) is an E1B 55-kilodalton protein-deficient replicating adenovirus that is currently in clinical trials as an antitumor agent. On the basis of the observation that the E1B 55kD gene product is able to bind to and inactivate p53, ONYX-015's mechanism of action is proposed to involve selective replication in and killing of p53-deficient cells. While its efficacy as a therapeutic agent appears evident, the virus's mechanism of cellular selectivity, including a possible role of p53 in this regard, is less clear. Indeed, there have been a number of recent reports suggesting that the p53 status of target cells does not reliably predict ONYX-015 replication or cell killing. To address the role of p53 in ONYX-015 selectivity, we have undertaken a rigorous analysis of the behavior of this virus in small airway-derived primary human epithelial cells expressing either dominant-negative or gain-of-function mutant p53 genes. Examination of small airway epithelial cells expressing a variety of p53 mutant alleles revealed that while all were able to inhibit endogenous p53 activity, only one allele examined, 248W, demonstrated a markedly increased ability to facilitate ONYX-015 replication. This allele is a member of a group of p53 mutants (know as class I mutants) characterized by retention of global structural conformation but loss of DNA-binding activity. These observations indicate that the nature of the p53 mutation affects ONYX-015 replication, help reconcile disparate published findings, and may provide criteria by which to direct clinical application of ONYX-015.

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Rockwell, Nathan C., Wei Yang, Nicole M. Warrington, Max V. Staller, Malachi Griffith, Obi L. Griffith, Christina A. Gurnett, Barak A. Cohen, Dustin Baldridge, and Joshua B. Rubin. "Sex- and Mutation-Specific p53 Gain-of-Function Activity in Gliomagenesis." Cancer Research Communications 1, no. 3 (December 2021): 148–63. http://dx.doi.org/10.1158/2767-9764.crc-21-0026.

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In cancer, missense mutations in the DNA-binding domain of TP53 are common. They abrogate canonical p53 activity and frequently confer gain-of-oncogenic function (GOF) through localization of transcriptionally active mutant p53 to noncanonical genes. We found that several recurring p53 mutations exhibit a sex difference in frequency in patients with glioblastoma (GBM). In vitro and in vivo analysis of three mutations, p53R172H, p53Y202C, and p53Y217C, revealed unique interactions between cellular sex and p53 GOF mutations that determined each mutation's ability to transform male versus female primary mouse astrocytes. These phenotypic differences were correlated with sex- and p53 mutation–specific patterns of genomic localization to the transcriptional start sites of upregulated genes belonging to core cancer pathways. The promoter regions of these genes exhibited a sex difference in enrichment for different transcription factor DNA-binding motifs. Together, our data establish a novel mechanism for sex-specific mutant p53 GOF activity in GBM with implications for all cancer. Significance: Sex differences in cancer, including glioblastoma, have been observed in both incidence and outcome. We reveal that TP53, the most commonly mutated gene in cancer, contributes to sex differences through differential GOF activity. This discovery has critical implications for our understanding of p53 mutations and the importance of sex as a biological variable.

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Roszkowska, Katarzyna A., Aleksandra Piecuch, Maria Sady, Zdzisław Gajewski, and Sylwia Flis. "Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches." International Journal of Molecular Sciences 23, no. 21 (October 31, 2022): 13287. http://dx.doi.org/10.3390/ijms232113287.

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Continuous development of personalized treatments is undoubtedly beneficial for oncogenic patients’ comfort and survival rate. Mutant TP53 is associated with a worse prognosis due to the occurrence of metastases, increased chemoresistance, and tumor growth. Currently, numerous compounds capable of p53 reactivation or the destabilization of mutant p53 are being investigated. Several of them, APR-246, COTI-2, SAHA, and PEITC, were approved for clinical trials. This review focuses on these novel therapeutic opportunities, their mechanisms of action, and their significance for potential medical application.

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Schulz-Heddergott, Ramona, and Ute Moll. "Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target." Cancers 10, no. 6 (June 7, 2018): 188. http://dx.doi.org/10.3390/cancers10060188.

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p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels.

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Frazier, Mark W., Xiaoping He, JinLing Wang, Zhengming Gu, John L. Cleveland, and Gerard P. Zambetti. "Activation of c-myc Gene Expression by Tumor-Derived p53 Mutants Requires a Discrete C-Terminal Domain." Molecular and Cellular Biology 18, no. 7 (July 1, 1998): 3735–43. http://dx.doi.org/10.1128/mcb.18.7.3735.

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ABSTRACT Mutation of the p53 tumor suppressor gene is the most common genetic alteration in human cancer, and tumors that express mutant p53 may be more aggressive and have a worse prognosis than p53-null cancers. Mutant p53 enhances tumorigenicity in the absence of a transdominant negative mechanism, and this tumor-promoting activity correlates with its ability to transactivate reporter genes in transient transfection assays. However, the mechanism by which mutant p53 functions in transactivation and its endogenous cellular targets that promote tumorigenicity are unknown. Here we report that (i) mutant p53 can regulate the expression of the endogenous c-mycgene and is a potent activator of the c-myc promoter; (ii) the region of mutant p53 responsiveness in the c-myc gene has been mapped to the 3′ end of exon 1; (iii) the mutant p53 response region is position and orientation dependent and therefore does not function as an enhancer; and (iv) transactivation by mutant p53 requires the C terminus, which is not essential for wild-type p53 transactivation. These data suggest that it may be possible to selectively inhibit mutant p53 gain of function and consequently reduce the tumorigenic potential of cancer cells. A possible mechanism for transactivation of the c-myc gene by mutant p53 is proposed.

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Donzelli, Sara, Francesca Biagioni, Francesca Fausti, Sabrina Strano, Giulia Fontemaggi, and Giovanni Blandino. "Oncogenomic Approaches in Exploring Gain of Function of Mutant p53." Current Genomics 9, no. 3 (May 1, 2008): 200–207. http://dx.doi.org/10.2174/138920208784340713.

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Xiong, S., H. Tu, M. Kollareddy, V. Pant, Q. Li, Y. Zhang, J. G. Jackson, et al. "Pla2g16 phospholipase mediates gain-of-function activities of mutant p53." Proceedings of the National Academy of Sciences 111, no. 30 (July 14, 2014): 11145–50. http://dx.doi.org/10.1073/pnas.1404139111.

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Yue, Xuetian, Yuhan Zhao, Yang Xu, Min Zheng, Zhaohui Feng, and Wenwei Hu. "Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy." Journal of Molecular Biology 429, no. 11 (June 2017): 1595–606. http://dx.doi.org/10.1016/j.jmb.2017.03.030.

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Zhang, Y., S. V. Coillie, J.-Y. Fang, and J. Xu. "Gain of function of mutant p53: R282W on the peak?" Oncogenesis 5, no. 2 (February 2016): e196-e196. http://dx.doi.org/10.1038/oncsis.2016.8.

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Yamamoto, Satomi, and Tomoo Iwakuma. "Regulators of Oncogenic Mutant TP53 Gain of Function." Cancers 11, no. 1 (December 20, 2018): 4. http://dx.doi.org/10.3390/cancers11010004.

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The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53.

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Deppert, Wolfgang, Thomas G�hler, Hisashi Koga, and Ella Kim. "Mutant p53: ?gain of function? through perturbation of nuclear structure and function?" Journal of Cellular Biochemistry 79, S35 (2000): 115–22. http://dx.doi.org/10.1002/1097-4644(2000)79:35+<115::aid-jcb1134>3.0.co;2-u.

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Rockwell, Nathan, Nicole Warrington, and Joshua Rubin. "CBIO-22. p53 GAIN-OF-FUNCTION MUTATIONS DRIVE SEX SPECIFIC EFFECTS ON GLIOMA TUMORIGENESIS." Neuro-Oncology 22, Supplement_2 (November 2020): ii20. http://dx.doi.org/10.1093/neuonc/noaa215.082.

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Abstract Sex differences in malignant brain tumors are well-established: Males exhibit greater incidence and poorer survival. Understanding the biology behind these sex differences requires investigation of the pathways known to drive gliomagenesis. The transcription factor TP53 (p53) is one of the most commonly mutated genes in glioblastoma. Most p53 mutations are missense mutations in the DNA-binding domain that lead to the expression of a full length mutant p53 protein. These mutations can endow p53 with oncogenic gains-of-function through aberrant DNA binding and regulation of noncanonical cancer-promoting target genes. Previously, we analyzed patient mutation data and identified six p53 mutations with sex differences in prevalence. In this study, we developed an in vitro mutant p53 glioma model to investigate the sex specific effects of three p53 point mutations: R175H, Y205C, and Y220C (Mm R172H, Y202C, and Y217C respectively). Male and female astrocytes isolated from p53flox/- mouse pups were transduced with a retrovirus expressing mutant p53, followed by a lentivirus expressing CRE recombinase to remove the endogenous WTp53. We then assessed cell proliferation, clonogenicity, and in vivo tumorigenesis in these cells. All three mutations assayed displayed sex differences in proliferation, with male cells overexpressing p53:Y202C and p53:Y217C growing faster than female cells, and female cells overexpressing p53:R172H growing faster than male cells. Male Y202C and Y217C expressing astrocytes also exhibited a trend toward greater clonogenicity compared to female astrocytes. This observation is supported by higher expression of the stem cell markers SOX2 and NESTIN in the male cells. We performed parallel flank injections of male and female astrocytes expressing each mutation or p53 KO. Only male astrocytes expressing p53:Y202C or p53:Y217C and female astrocytes expressing p53:R172H mutation were able to form tumors in vivo. Together, these data support a sex specific gain-of-function phenotype for three different p53 mutations observed in glioma.

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Cai, Bi-He, Yun-Chien Hsu, Fang-Yu Yeh, Yu-Rou Lin, Rui-Yu Lu, Si-Jie Yu, Jei-Fu Shaw, et al. "P63 and P73 Activation in Cancers with p53 Mutation." Biomedicines 10, no. 7 (June 23, 2022): 1490. http://dx.doi.org/10.3390/biomedicines10071490.

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The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.

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Candelaria, Nicholes, Achuth Padmanabhan, Rainer Lanz, Kwong Wong, and JoAnne S. Richards. "P53 Gain-of-Function Mutants and Steroids in Ovarian Cancer Cell Metastasis." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A770—A771. http://dx.doi.org/10.1210/jendso/bvab048.1567.

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Abstract High-grade serous ovarian cancer (HGSOC) is a heterogeneous disease for which there currentlyis no cure. Because p53 is mutated in >90% of all ovarian cancer, we studied specific gain-of-function (GOF) p53 mutants and steroid hormones for tumor morphology and metastasis in vivo. For this, we analyzed ALST (WT p53), SKOV3 (p53 null), TYK-NU (p53-R175H), OVCAR3 (p53-R248Q) and OVCA420 (p53-R273H) cell line xenografts in Foxn1-/- mice. ALST cells failed tometastasize, likely due to the known apoptotic effects of WT p53. SKOV3 and the p53-GOF celllines metastasized to the omentum and exhibited distinct morphologies: SKOV3, epithelial-like;TYK-Nu, vascular-like; OVCAR3, epithelial/mesenchymal; and OVCA420 epithelial exclusive. Despite different morphologies and p53 status, each tumor type contained large, Polyploid GiantCancer Cells (PGCCs) that are stem-like cells undergoing endoreplication. A specificphosphorylated, active form of β−catenin (pCTNNB1-S31/S37/T41; pCTNNB1) co-localizedselectively with GOF p53 and the mitotic stress regulatory kinase pMSK1-T581 in mitotic cells andPGCCs, indicating that in addition to GOF p53 mutants, pCTNNB1 and pMSK1 play a role intumor progression. To determine if ALST cells could be rendered metastatic, the p53 GOFmutants R175H and R273H were stably expressed in these cells. Remarkably, the ALST(WT/R273H) cells, but not the ALST (WT/R175H) cells, formed solid tumors on the ovary, visceralfat and uterus; but not on the omentum where OVCA420 (p53-R273H) cells formed tumors. TheALST (WT/R273H) tumors harbored discreet populations of pCTNNB1+ mitotic cells and PGCCsand exhibited distinct growth-promoting responses to estradiol while showing growth-inhibitoryeffects of DHT and nuclear AR in the tumor-associated stromal cells. Stably expressing p53-R175H or p53-R273H GOF mutants in SKOV3 (p53 null) cells enhanced tumor progression withthe R273H mutant being most aggressive. The parental SKOV3 tumors also contained pCTNNB1that was associated with mitotic cells and PGCCs. In the SKOV3 p53-R175H cells - and moreimpressively in the p53-R273H cells - pCTNNB1 co-localized with p53 in PGCCs. Whereas ESR1staining was diffuse in the ALST-R273H cells, it was nuclear in the SKOV3 cell lines. However,tumor promotion by estrogen and inhibition by DHT were observed in each SKOV3 cell line,suggesting that stromal cells may also contribute to the steroid dependent effects. Collectively, 1)elevated levels of specific phosphorylated forms of CTNNB1 and MSK1 identify mitotic cells andPGCCs within the tumors and new targets for therapeutic approaches; 2) knowing the status ofp53, and the presence and localization of pCTNNB1 and pMSK1 and steroid hormone receptorsin ovarian tumors suggest combinatorial approaches should be considered to combat the mostlethal gynecological cancer. NIH-CA181808; NIH-HD097321 (JSR).

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Kalo, Eyal, Yosef Buganim, Keren E. Shapira, Hilla Besserglick, Naomi Goldfinger, Lilach Weisz, Perry Stambolsky, Yoav I. Henis, and Varda Rotter. "Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II." Molecular and Cellular Biology 27, no. 23 (September 17, 2007): 8228–42. http://dx.doi.org/10.1128/mcb.00374-07.

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ABSTRACT Both transforming growth factor beta (TGF-β) and p53 have been shown to control normal cell growth. Acquired mutations either in the TGF-β signaling pathway or in the p53 protein were shown to induce malignant transformation. Recently, cross talk between wild-type p53 and the TGF-β pathway was observed. The notion that mutant p53 interferes with the wild-type p53-induced pathway and acts by a “gain-of-function” mechanism prompted us to investigate the effect of mutant p53 on the TGF-β-induced pathway. In this study, we show that cells expressing mutant p53 lost their sensitivity to TGF-β1, as observed by less cell migration and a reduction in wound healing. We found that mutant p53 attenuates TGF-β1 signaling. This was exhibited by a reduction in SMAD2/3 phosphorylation and an inhibition of both the formation of SMAD2/SMAD4 complexes and the translocation of SMAD4 to the cell nucleus. Furthermore, we found that mutant p53 attenuates the TGF-β1-induced transcription activity of SMAD2/3 proteins. In searching for the mechanism that underlies this attenuation, we found that mutant p53 reduces the expression of TGF-β receptor type II. These data provide important insights into the molecular mechanisms that underlie mutant p53 “gain of function” pertaining to the TGF-β signaling pathway.

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He, Chao, Lun Li, Xuan Guan, Li Xiong, and Xiongying Miao. "Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy." Chemotherapy 62, no. 1 (June 21, 2016): 43–53. http://dx.doi.org/10.1159/000446361.

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Purpose: To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. Methods: We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. Results: Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents. Conclusion: mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.

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Yang, Hao, Ke Zhang, Yusheng Guo, Xin Guo, Kailong Hou, Jing Hou, Ying Luo, Jing Liu, and Shuting Jia. "Gain-of-Function p53N236S Mutation Drives the Bypassing of HRasV12-Induced Cellular Senescence via PGC–1α." International Journal of Molecular Sciences 24, no. 4 (February 14, 2023): 3790. http://dx.doi.org/10.3390/ijms24043790.

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One of the key steps in tumorigenic transformation is immortalization in which cells bypass cancer-initiating barriers such as senescence. Senescence can be triggered by either telomere erosion or oncogenic stress (oncogene-induced senescence, OIS) and undergo p53- or Rb-dependent cell cycle arrest. The tumor suppressor p53 is mutated in 50% of human cancers. In this study, we generated p53N236S (p53S) mutant knock-in mice and observed that p53S heterozygous mouse embryonic fibroblasts (p53S/+) escaped HRasV12-induced senescence after subculture in vitro and formed tumors after subcutaneous injection into severe combined immune deficiency (SCID) mice. We found that p53S increased the level and nuclear translocation of PGC–1α in late-stage p53S/++Ras cells (LS cells, which bypassed the OIS). The increase in PGC–1α promoted the biosynthesis and function of mitochondria in LS cells by inhibiting senescence-associated reactive oxygen species (ROS) and ROS-induced autophagy. In addition, p53S regulated the interaction between PGC–1α and PPARγ and promoted lipid synthesis, which may indicate an auxiliary pathway for facilitating cell escape from aging. Our results illuminate the mechanisms underlying p53S mutant-regulated senescence bypass and demonstrate the role played by PGC–1α in this process.

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Annor, George Kwakye. "Abstract P5-09-02: Tetrameric and monomeric gain-of-function mutant p53 interacts with chromatin." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–09–02—P5–09–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-09-02.

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Abstract In 80% of triple-negative breast cancers (TNBC) the TP53 gene is mutated, with a high occurrence of missense changed in the DNA binding domain. These mutations lead to loss of wild-type p53 (wtp53) function and some also create mutant p53 (mtp53) proteins with novel gain-of-function (GOF) tumor-promoting capabilities. We previously reported that mtp53 R273H interacts with replication-associated proteins including MCM2-7 and poly ADP-ribose polymerase (PARP1). Moreover, mtp53 is found on actively replicating nascent DNA. What remains unclear is which domains of mtp53 R273H are responsible for the protein’s chromatin-based replication activities. In this study, we tested whether the oligomerization state of mtp53 plays a role in oncogenic GOF activities. We destabilized tetramer formation by using site-directed mutagenesis to introduce oligomerization domain (OD) point mutations A347D, R337C, or L344P. The site-directed mutagenesis constructs were transiently transfected into p53-/- mammalian cell lines to evaluate the altered functions. The oligomerization state of mtp53 was assessed via glutaraldehyde crosslinking and western blot analyses. Western blot and qPCR analyses were used to test how OD mutations in plasmids expressing either wtp53 or R273H mtp53 regulated the targets p21, CDC7 and RRM2. We used chromatin fractionation and western blot analyses to compare the chromatin association of the R273H mtp53 (with variable OD mutants), PARP1, and MCM2 to assess how destabilizing tetramer formation influenced chromatin interactions. Compared to the tetrameric versions of wildtype (wt) and mutant (mt) p53, the wtp53-A347D and R273H-A347D were predominantly dimers, while wtp53-R337C, wtp53-L344P, mtp53 R273H-R337C, and mtp53R273H-L344P were predominantly monomers. When wtp53 tetramerization was blocked so was its ability to activate the cyclin-dependent kinase p21/waf. Interestingly, all oligomerization forms of mtp53 localized to the chromatin suggesting GOF does not require tetramer formation for all functions. Strikingly, all oligomerization mutants of R273H mtp53, compared to the tetrameric mtp53, had a stronger interaction with MCM2. When we examined the mtp53 GOF transcriptional target we found that only tetrameric mtp53 R273H activated the target gene RRM2. Our findings suggest that destabilizing tetramer formation reduced certain mtp53 R273H GOF oncogenic activities while activating others. These changes of functions require examination in the context of triple-negative breast cancers. Citation Format: George Kwakye Annor. Tetrameric and monomeric gain-of-function mutant p53 interacts with chromatin [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-09-02.

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Gomes, Ana Sara, Helena Ramos, Alberto Inga, Emília Sousa, and Lucília Saraiva. "Structural and Drug Targeting Insights on Mutant p53." Cancers 13, no. 13 (July 3, 2021): 3344. http://dx.doi.org/10.3390/cancers13133344.

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p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53.

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Stein, Yan, Ronit Aloni-Grinstein, and Varda Rotter. "Mutant p53—a potential player in shaping the tumor–stroma crosstalk." Journal of Molecular Cell Biology 11, no. 7 (July 2019): 600–604. http://dx.doi.org/10.1093/jmcb/mjz071.

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Abstract A plethora of studies suggest that the non-transformed cellular and non-cellular components of the tumor, collectively known as the tumor microenvironment, have a significant impact on the tumorigenic process. It was suggested that the microenvironment, which initially restricts tumor development, is recruited by the tumor and maintains a crosstalk that further promotes cancer progression. Indeed, many of the molecules that participate in the tumor–stroma crosstalk have been characterized. However, the crucial factors that are responsible for the initiation of this crosstalk or the ‘recruitment’ process remain poorly understood. We propose that oncogenes themselves may influence the ‘recruitment’ of the stromal cells, while focusing on mutant p53. Apart from losing its tumor-suppressing properties, mutant p53 gains novel oncogenic functions, a phenomenon dubbed mutant p53 gain of function (GOF). Here, we discuss possible ways in which mutant p53 may modulate the microenvironment in order to promote tumorigenesis. We thus propose that mutant p53 may serve as a key player in the modulation of the tumor–stroma crosstalk in a way that benefits the tumor. Further elucidation of these ‘recruitment’ processes, dictated by mutant p53, may be utilized for tailoring personalized therapeutic approaches for patients with tumors that harbor p53 mutation.

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Levine, Arnold J. "Targeting Therapies for the p53 Protein in Cancer Treatments." Annual Review of Cancer Biology 3, no. 1 (March 4, 2019): 21–34. http://dx.doi.org/10.1146/annurev-cancerbio-030518-055455.

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Half of all human cancers contain TP53 mutations, and in many other cancers, the function of the p53 protein is compromised. The diversity of these mutations and phenotypes presents a challenge to the development of drugs that target p53 mutant cancer cells. This review describes the rationale for many different approaches in the development of p53 targeted therapies: ( a) viruses and gene therapies, ( b) increased levels and activity of wild-type p53 proteins in cancer cells, ( c) p53 protein gain-of-function inhibitors, ( d) p53 protein loss-of-function structural correctors, ( e) mutant p53 protein synthetic lethal drugs interfering with the p53 pathway, and ( f) cellular immune responses to mutant p53 protein antigens. As these types of therapies are developed, tested, and evaluated, the best of them will have a significant impact upon cancer treatments and possibly prevention.

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Bellazzo, Arianna, Giulio Di Minin, and Licio Collavin. "Cytoplasmic gain-of-function mutant p53 contributes to inflammation-associated cancer." Molecular & Cellular Oncology 2, no. 4 (January 23, 2015): e1002719. http://dx.doi.org/10.1080/23723556.2014.1002719.

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Walerych, Dawid, Kamil Lisek, and Giannino Del Sal. "Multi-omics reveals global effects of mutant p53 gain-of-function." Cell Cycle 15, no. 22 (August 13, 2016): 3009–10. http://dx.doi.org/10.1080/15384101.2016.1215703.

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Yan, Wensheng, and Xinbin Chen. "Characterization of Functional Domains Necessary for Mutant p53 Gain of Function." Journal of Biological Chemistry 285, no. 19 (March 8, 2010): 14229–38. http://dx.doi.org/10.1074/jbc.m109.097253.

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Billant, Olivier, Gaëlle Friocourt, Pierre Roux, and Cécile Voisset. "p53, A Victim of the Prion Fashion." Cancers 13, no. 2 (January 13, 2021): 269. http://dx.doi.org/10.3390/cancers13020269.

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Identified in the late 1970s as an oncogene, a driving force leading to tumor development, p53 turned out to be a key tumor suppressor gene. Now p53 is considered a master gene regulating the transcription of over 3000 target genes and controlling a remarkable number of cellular functions. The elevated prevalence of p53 mutations in human cancers has led to a recurring questioning about the roles of mutant p53 proteins and their functional consequences. Both mutants and isoforms of p53 have been attributed dominant-negative and gain of function properties among which is the ability to form amyloid aggregates and behave in a prion-like manner. This report challenges the ongoing “prion p53” hypothesis by reviewing evidence of p53 behavior in light of our current knowledge regarding amyloid proteins, prionoids and prions.

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Blandino, Giovanni, Arnold J. Levine, and Moshe Oren. "Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy." Oncogene 18, no. 2 (January 1999): 477–85. http://dx.doi.org/10.1038/sj.onc.1202314.

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Zalcenstein, Amir, Perry Stambolsky, Lilach Weisz, Martina Müller, David Wallach, Tanya M. Goncharov, Peter H. Krammer, Varda Rotter, and Moshe Oren. "Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by tumor-associated p53 mutants." Oncogene 22, no. 36 (August 2003): 5667–76. http://dx.doi.org/10.1038/sj.onc.1206724.

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Journal articles on the topic 'Mutant p53 gain of function'

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