scholarly journals Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer

2022 ◽  
Author(s):  
Shengliang Zhang ◽  
Lindsey Carlsen ◽  
Liz Hernandez Borrero ◽  
Attila A. Seyhan ◽  
Xiaobing Tian ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Target Genes ◽  
P53 Protein ◽  
Suppressor Gene ◽  
Functional Restoration ◽  
Mutant P53 ◽  
Combination Therapies ◽  
Loss Of Function ◽  
Wild Type ◽  
Promising Target

TP53 is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli and upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. P53 is the most frequently mutated gene in tumors with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) which promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for 1) boosting p53 activity in cancer, 2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, 3) targeting p53 in immunotherapy, and 4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.

scholarly journals Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 98
Author(s):  
Paola Menichini ◽  
Paola Monti ◽  
Andrea Speciale ◽  
Giovanna Cutrona ◽  
Serena Matis ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Cell Metabolism ◽  
Therapy Response ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Lower Percentage ◽  
Mutant P53 ◽  
Wild Type ◽  
Antitumor Effects ◽  
Tp53 Tumor Suppressor Gene

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1Met/APR246 and describes their potential use in hematological malignancies.

Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae

1992 ◽  
Vol 12 (3) ◽  
pp. 1357-1365
Author(s):  
J M Nigro ◽  
R Sikorski ◽  
S I Reed ◽  
B Vogelstein
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Growth Inhibition ◽  
Mammalian Cells ◽  
P53 Protein ◽  
Inducible Promoter ◽  
Mutant P53 ◽  
Wild Type ◽  
Growth Inhibitory Activity ◽  
Wild Type P53 ◽  
P53 Genes

Human wild-type and mutant p53 genes were expressed under the control of a galactose-inducible promoter in Saccharomyces cerevisiae. The growth rate of the yeast was reduced in cells expressing wild-type p53, whereas cells transformed with mutant p53 genes derived from human tumors were less affected. Coexpression of the normal p53 protein with the human cell cycle-regulated protein kinase CDC2Hs resulted in much more pronounced growth inhibition that for p53 alone. Cells expressing p53 and CDC2Hs were partially arrested in G1, as determined by morphological analysis and flow cytometry. p53 was phosphorylated when expressed in the yeast, but differences in phosphorylation did not explain the growth inhibition attributable to coexpression of p53 and CDC2Hs. These results suggest that wild-type p53 has a growth-inhibitory activity in S. cerevisiae similar to that observed in mammalian cells and suggests that this yeast may provide a useful model for defining the pathways through which p53 acts.

scholarly journals Crosstalk between p53 and TGF-β Signalling

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Rebecca Elston ◽  
Gareth J. Inman
Keyword(s):  
Transcriptional Activation ◽  
Cancer Biology ◽  
Target Genes ◽  
Tumour Progression ◽  
Signal Transduction Pathway ◽  
Mirna Biogenesis ◽  
Mutant P53 ◽  
Wild Type ◽  
P53 Family ◽  
Wild Type P53

Wild-type p53 and TGF-β are key tumour suppressors which regulate an array of cellular responses. TGF-β signals in part via the Smad signal transduction pathway. Wild-type p53 and Smads physically interact and coordinately induce transcription of a number of key tumour suppressive genes. Conversely mutant p53 generally subverts tumour suppressive TGF-β responses, diminishing transcriptional activation of key TGF-β target genes. Mutant p53 can also interact with Smads and this enables complex formation with the p53 family member p63 and blocks p63-mediated activation of metastasis suppressing genes to promote tumour progression. p53 and Smad function may also overlap during miRNA biogenesis as they can interact with the same components of the Drosha miRNA processing complex to promote maturation of specific subsets of miRNAs. This paper investigates the crosstalk between p53 and TGF-β signalling and the potential roles this plays in cancer biology.

scholarly journals The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth

1993 ◽  
Vol 13 (1) ◽  
pp. 301-306 ◽  
Author(s):  
C A Finlay
Keyword(s):  
P53 Protein ◽  
Mutant P53 ◽  
Wild Type ◽  
Rat Embryo ◽  
Ras Gene ◽  
Double Minute ◽  
Murine Double Minute ◽  
Low Levels ◽  
Wild Type P53 ◽  
P53 Genes

Expression of a p53-associated protein, Mdm-2 (murine double minute-2), can inhibit p53-mediated transactivation. In this study, overexpression of the Mdm-2 protein was found to result in the immortalization of primary rat embryo fibroblasts (REFs) and, in conjunction with an activated ras gene, in the transformation of REFs. The effect of wild-type p53 on the transforming properties of mdm-2 was determined by transfecting REFs with ras, mdm-2, and normal p53 genes. Transfection with ras plus mdm-2 plus wild-type p53 resulted in a 50% reduction in the number of transformed foci (relative to the level for ras plus mdm-2); however, more than half (9 of 17) of the cell lines derived from these foci expressed low levels of a murine p53 protein with the characteristics of a wild-type p53. These results are in contrast to previous studies which demonstrated that even minimal levels of wild-type p53 are not tolerated in cells transformed by ras plus myc, E1A, or mutant p53. The mdm-2 oncogene can overcome the previously demonstrated growth-suppressive properties of p53.

scholarly journals TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma

Blood ◽  
2018 ◽  
Vol 131 (25) ◽  
pp. 2789-2802 ◽  
Author(s):  
Alexander Jethwa ◽  
Mikołaj Słabicki ◽  
Jennifer Hüllein ◽  
Marius Jentzsch ◽  
Vineet Dalal ◽  
...  
Keyword(s):  
Protein Stability ◽  
P53 Protein ◽  
Mutant P53 ◽  
Wild Type ◽  
Therapeutic Targeting ◽  
Key Points ◽  
Wild Type P53

Key Points The HAT complex member TRRAP is vital for maintaining high p53 levels by shielding it against the natural p53 degradation machinery. Acetylation-modifying complexes regulate p53 protein stability, which may provide a basis for therapeutic targeting of mutant p53.

scholarly journals MON-717 Novel GLI2 Mutations Identified in Pediatric Patients with Combined Pituitary Hormone Deficiency: One Gene, Various Genotypes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sebastian A Vishnopolska ◽  
Debora Braslavsky ◽  
Ana Claudia Keselman ◽  
Ignacio Bergada ◽  
Roxana M Marino ◽  
...  
Keyword(s):  
Cell Line ◽  
Target Genes ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Loss Of Function ◽  
Wild Type ◽  
Gfp Expression ◽  
Shh Signaling ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency

Abstract Combined pituitary hormone deficiency (CPHD) is an important clinical problem caused by mutations in more than 30 different genes. Six genes in the Sonic Hedgehog (SHH) signalling pathway are reported to cause CPHD. SHH signaling is essential to induce pituitary cell identity in cells of Rathke’s pouch by stimulating expression of the transcription factors Lhx3 and Lhx4. In the absence of SHH signaling, a repressive isoform of the transcription factor GLI2 (Gli-Kruppel family member 2) suppresses gene expression. In the presence of SHH signaling, the activating form of GLI2 gains access to the nucleus and induces expression of downstream target genes. Heterozygous GLI2 loss of function mutations are found in patients with holoprosencephaly (HPE), HPE-like phenotypes associated with pituitary anomalies, and combined pituitary hormone deficiency with or without other extra-pituitary findings. We sought to identify the cause of CPHD in 171 unrelated patients diagnosed with or without extra-pituitary manifestations that were recruited from several Argentinean medical centers. We conducted panel sequencing, and identified GLI2 heterozygous variants that were rare and predicted to be deleterious in two unrelated patients, (p.L761P and p.1404Lfs) and a single, heterozygous, rare, likely deleterious GLI2 variant identified by exome sequencing (p.A203T). p.L761P and p.A203T variants were previously reported as candidates for HPE/CPHD, no functional studies were carried out to determine the effect of the variants on the gene function. We performed functional analysis of these variants using a mammalian cell line (NIH/3T3-CG) previously engineered to be a sensor for SHH signaling. It was stably transfected with a reporter gene that expresses GFP in response to GLI2 activation by a SHH agonist. We modified this cell line to assay GLI2 variants. We created a homozygous knock out of both endogenous Gli2 genes using CRISPR-Cas9 editing, and individual cell clones were selected for loss of GFP expression in response to SHH agonist treatment by FACS. We verified that transfecting the knockout cells with wild type Gli2 restored SHH responsive GFP expression. We assayed the ability of three patient GLI2 variants to rescue GFP expression and SHH agonist responsiveness and found that all three failed to fully rescue to wild type levels. This supports the hypothesis that the GLI2 variants in three CPHD patients are likely pathogenic. Thus, we identified three likely pathogenic GLI2 mutations in CPHD patients from Argentina. The variable phenotype of patients with GLI2 mutations worldwide could be caused by variation in other genes, environmental exposures, maternal effects, and/or epigenetic factors.

scholarly journals CP-31398 Restores DNA-binding Activity to Mutant p53in Vitrobut Does Not Affect p53 Homologs p63 and p73

2004 ◽  
Vol 279 (44) ◽  
pp. 45887-45896 ◽  
Author(s):  
Mark J. Demma ◽  
Serena Wong ◽  
Eugene Maxwell ◽  
Bimalendu Dasmahapatra
Keyword(s):  
Dna Binding ◽  
Mammalian Cells ◽  
P53 Protein ◽  
Binding Activity ◽  
Mutant P53 ◽  
Dependent Manner ◽  
Wild Type ◽  
Dna Binding Activity

The p53 protein plays a major role in the maintenance of genome stability in mammalian cells. Mutations of p53 occur in over 50% of all cancers and are indicative of highly aggressive cancers that are hard to treat. Recently, there has been a high degree of interest in therapeutic approaches to restore growth suppression functions to mutant p53. Several compounds have been reported to restore wild type function to mutant p53. One such compound, CP-31398, has been shown effectivein vivo, but questions have arisen to whether it actually affects p53. Here we show that mutant p53, isolated from cells treated with CP-31398, is capable of binding to p53 response elementsin vitro. We also show the compound restores DNA-binding activity to mutant p53 in cells as determined by a chromatin immunoprecipitation assay. In addition, using purified p53 core domain from two different hotspot mutants (R273H and R249S), we show that CP-31398 can restore DNA-binding activity in a dose-dependent manner. Using a quantitative DNA binding assay, we also show that CP-31398 increases significantly the amount of mutant p53 that binds to cognate DNA (Bmax) and its affinity (Kd) for DNA. The compound, however, does not affect the affinity (Kdvalue) of wild type p53 for DNA and only increasesBmaxslightly. In a similar assay PRIMA1 does not have any effect on p53 core DNA-binding activity. We also show that CP-31398 had no effect on the DNA-binding activity of p53 homologs p63 and p73.

Single chain antibody against the common epitope of mutant p53 restores wild-type activity to mutant p53 protein

FEBS Letters ◽  
2005 ◽  
Vol 579 (25) ◽  
pp. 5609-5615 ◽  
Author(s):  
Sara Orgad ◽  
Naomi Goldfinger ◽  
Gerald Cohen ◽  
Varda Rotter ◽  
Beka Solomon
Keyword(s):  
P53 Protein ◽  
Mutant P53 ◽  
Wild Type ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Type Activity ◽  
The Common

scholarly journals NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Romaric Bouveret ◽  
Ashley J Waardenberg ◽  
Nicole Schonrock ◽  
Mirana Ramialison ◽  
Tram Doan ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Regulatory Networks ◽  
Congenital Heart ◽  
Target Genes ◽  
Loss Of Function ◽  
Wild Type ◽  
Interaction Domain ◽  
Ets Proteins ◽  
Gene Regulatory

We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformation-specific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD). Off-targets of NKX2-5 mutants, but not those of an NKX2-5 YRD mutant, showed overrepresentation of ETS binding sites and were occupied by ETS proteins, as determined by DamID. Analysis of kernel transcription factor and ETS targets show that ETS proteins are highly embedded within the cardiac gene regulatory network. Our study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.

scholarly journals The Ribosome Biogenesis Factor Ltv1 Is Essential for Digestive Organ Development and Definitive Hematopoiesis in Zebrafish

2021 ◽  
Vol 9 ◽  
Author(s):  
Chong Zhang ◽  
Rui Huang ◽  
Xirui Ma ◽  
Jiehui Chen ◽  
Xinlu Han ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Target Genes ◽  
P53 Protein ◽  
Ribosomal Subunit ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Independent Manner ◽  
Hematopoietic Stem ◽  
Digestive Organs ◽  
Stem And Progenitor Cells

Ribosome biogenesis is a fundamental activity in cells. Ribosomal dysfunction underlies a category of diseases called ribosomopathies in humans. The symptomatic characteristics of ribosomopathies often include abnormalities in craniofacial skeletons, digestive organs, and hematopoiesis. Consistently, disruptions of ribosome biogenesis in animals are deleterious to embryonic development with hypoplasia of digestive organs and/or impaired hematopoiesis. In this study, ltv1, a gene involved in the small ribosomal subunit assembly, was knocked out in zebrafish by clustered regularly interspaced short palindromic repeats (CRISPRs)/CRISPR associated protein 9 (Cas9) technology. The recessive lethal mutation resulted in disrupted ribosome biogenesis, and ltv1Δ14/Δ14 embryos displayed hypoplastic craniofacial cartilage, digestive organs, and hematopoiesis. In addition, we showed that the impaired cell proliferation, instead of apoptosis, led to the defects in exocrine pancreas and hematopoietic stem and progenitor cells (HSPCs) in ltv1Δ14/Δ14 embryos. It was reported that loss of function of genes associated with ribosome biogenesis often caused phenotypes in a P53-dependent manner. In ltv1Δ14/Δ14 embryos, both P53 protein level and the expression of p53 target genes, Δ113p53 and p21, were upregulated. However, knockdown of p53 failed to rescue the phenotypes in ltv1Δ14/Δ14 larvae. Taken together, our data demonstrate that LTV1 ribosome biogenesis factor (Ltv1) plays an essential role in digestive organs and hematopoiesis development in zebrafish in a P53-independent manner.

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