Journal articles: 'P53'

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Li, Muyang, Fredrick Philantrope, Alexandra Diot, Jean-Christophe Bourdon, and Patricia Thompson. "A Novel Role of SMG1 in Cholesterol Homeostasis That Depends Partially on p53 Alternative Splicing." Cancers 14, no. 13 (July 2, 2022): 3255. http://dx.doi.org/10.3390/cancers14133255.

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SMG1, a phosphatidylinositol 3-kinase-related kinase (PIKK), essential in nonsense-mediated RNA decay (NMD), also regulates p53, including the alternative splicing of p53 isoforms reported to retain p53 functions. We confirm that SMG1 inhibition in MCF7 tumor cells induces p53β and show p53γ increase. Inhibiting SMG1, but not UPF1 (a core factor in NMD), upregulated several cholesterol pathway genes. SMG1 knockdown significantly increased ABCA1, a cholesterol efflux pump shown to be positively regulated by full-length p53 (p53α). An investigation of RASSF1C, an NMD target, increased following SMG1 inhibition and reported to inhibit miR-33a-5p, a canonical ABCA1-inhibiting miRNA, did not explain the ABCA1 results. ABCA1 upregulation following SMG1 knockdown was inhibited by p53β siRNA with greatest inhibition when p53α and p53β were jointly suppressed, while p53γ siRNA had no effect. In contrast, increased expression of MVD, a cholesterol synthesis gene upregulated in p53 deficient backgrounds, was sensitive to combined targeting of p53α and p53γ. Phenotypically, we observed increased intracellular cholesterol and enhanced sensitivity of MCF7 to growth inhibitory effects of cholesterol-lowering Fatostatin following SMG1 inhibition. Our results suggest deregulation of cholesterol pathway genes following SMG1 knockdown may involve alternative p53 programming, possibly resulting from differential effects of p53 isoforms on cholesterol gene expression.

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Gudikote, Jayanthi, Tina Cascone, Alissa Poteete, Piyada Sitthideatphaiboon, Sonia Patel, Yan Yang, Fahao Zhang, et al. "Abstract 5733: Targeting nonsense-mediated decay restores p53 function in HPV-associated head and neck cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5733. http://dx.doi.org/10.1158/1538-7445.am2022-5733.

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Abstract HPV-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) tumors typically have p53 loss due to the activity of the human papillomavirus (HPV)-encoded E6 protein and the E6-associated protein (HPVE6-AP) which mediate the degradation of wild-type (WT) p53 (p53α). The loss of p53 is thought to be a major contributor to the pathogenesis of HPV+ HNSCC, which comprise approximately 35% of all HNSCC. Currently, standard care for HPV+HNSCC includes radiation and chemotherapy. However long-term toxicity related to these treatments is a concern, and there is a need for newer therapeutic strategies. Previously, we reported that two alternatively spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising of exons 1 to 9β or 9γ, respectively) are degraded by nonsense-mediated decay (NMD), a regulator of aberrant mRNA stability. Here, using HPV+HNSCC cell line models, we show that NMD inhibition rescues p53β/γ isoforms and activates p53 pathway. Furthermore, we show that p53β/γ isoforms are more stable compared to p53α in these cells, with reduced vulnerabililty to HPVE6-AP- mediated degradation, and that p53β/γ isoforms contribute to increased expression of p53 transcriptional targets p21 and PUMA following NMD inhibition. Consistent with p53 pathway activation, NMD inhibition enhanced radiosensitivity of HNSCC cells. NMD inhibition attenuated colony forming ability and disrupted cell cycle progression. To evaluate the therapeutic implications of NMD inhibition, we assessed the in vivo growth of HPV+ UMSCC47 tumors. Nude mice were injected with UMSCC47 cells either subcutaneously or orthotopically in the tongue and randomized to receive vehicle or with an NMD inhibitor. In both tumor models, we observed a significant reduction in tumor volume with NMD inhibition as compared to the vehicle-treated animals. To investigate whether NMD inhibition induced the expression of p53β/γ isoforms and activated the p53 pathway in vivo, we collected tumor tissues from animals and evaluated expression of p53 isoforms and transcriptional targets by RT-PCR. We observed increased expression of p53γ, p21, GADD45A and PUMA mRNAs in NMD inhibitor treated UMSCC47 tumors, compared to their respective vehicle treated controls. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in major subgroups of p53-deficient HPV+ HNSCC tumors. Citation Format: Jayanthi Gudikote, Tina Cascone, Alissa Poteete, Piyada Sitthideatphaiboon, Sonia Patel, Yan Yang, Fahao Zhang, Lerong Li, Li Shen, Monique Nilsson, Phillip Jones, Jing Wang, Jean-Christophe Bourdon, Faye M. Johnson, John V. Heymach. Targeting nonsense-mediated decay restores p53 function in HPV-associated head and neck cancers [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 5733.

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Prikhod’ko, Grigori G., Yan Wang, Ella Freulich, Carol Prives, and Lois K. Miller. "Baculovirus p33 Binds Human p53 and Enhances p53-Mediated Apoptosis." Journal of Virology 73, no. 2 (February 1, 1999): 1227–34. http://dx.doi.org/10.1128/jvi.73.2.1227-1234.1999.

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ABSTRACT In vertebrates, p53 participates in numerous biological processes including cell cycle regulation, apoptosis, differentiation, and oncogenic transformation. When insect SF-21 cells were infected with a recombinant of the baculovirus Autographa californicanuclear polyhedrosis virus (AcMNPV) overexpressing human p53, p53 formed a stable complex with the product of the AcMNPV orf92, a novel protein p33. The interaction between p53 and p33 was further confirmed by immunoprecipitation studies. When individually expressed in SF-21 cells, human p53 localized mainly in the nucleus whereas baculovirus p33 displayed diffuse cytoplasmic staining and punctuate nuclear staining. However, coexpression of p33 with p53 resulted in exclusive nuclear localization of p33. In both SF-21 and TN-368 cells, p53 expression induced typical features of apoptosis including nuclear condensation and fragmentation, oligonucleosomal ladder formation, cell surface blebbing, and apoptotic body formation. Coexpression of p53 with a baculovirus inhibitor of apoptosis, p35, OpIAP, or CpIAP, blocked apoptosis, whereas coexpression with p33 enhanced p53-mediated apoptosis approximately twofold. Expression of p53 in SF-21 cells stably expressing OpIAP inhibited cell growth in the presence or absence of p33. Thus, human p53 can influence both insect cell growth and death and baculovirus p33 can modulate the death-inducing effects of p53.

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Haaland, Ingvild, Sigrun M. Hjelle, Håkon Reikvam, André Sulen, Anita Ryningen, Emmet McCormack, Øystein Bruserud, and Bjørn Tore Gjertsen. "p53 Protein Isoform Profiles in AML: Correlation with Distinct Differentiation Stages and Response to Epigenetic Differentiation Therapy." Cells 10, no. 4 (April 7, 2021): 833. http://dx.doi.org/10.3390/cells10040833.

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p53 protein isoform expression has been found to correlate with prognosis and chemotherapy response in acute myeloid leukemia (AML). We aimed to investigate how p53 protein isoforms are modulated during epigenetic differentiation therapy in AML, and if p53 isoform expression could be a potential biomarker for predicting a response to this treatment. p53 full-length (FL), p53β and p53γ protein isoforms were analyzed by 1D and 2D gel immunoblots in AML cell lines, primary AML cells from untreated patients and AML cells from patients before and after treatment with valproic acid (VPA), all-trans retinoic acid (ATRA) and theophylline. Furthermore, global gene expression profiling analysis was performed on samples from the clinical protocol. Correlation analyses were performed between p53 protein isoform expression and in vitro VPA sensitivity and FAB (French–American–British) class in primary AML cells. The results show downregulation of p53β/γ and upregulation of p53FL in AML cell lines treated with VPA, and in some of the patients treated with differentiation therapy. p53FL positively correlated with in vitro VPA sensitivity and the FAB class of AML, while p53β/γ isoforms negatively correlated with the same. Our results indicate that p53 protein isoforms are modulated by and may predict sensitivity to differentiation therapy in AML.

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Ashcroft, Margaret, Michael H. G. Kubbutat, and Karen H. Vousden. "Regulation of p53 Function and Stability by Phosphorylation." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 1751–58. http://dx.doi.org/10.1128/mcb.19.3.1751.

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ABSTRACT The p53 tumor suppressor protein can be phosphorylated at several sites within the N- and C-terminal domains, and several protein kinases have been shown to phosphorylate p53 in vitro. In this study, we examined the activity of p53 proteins with combined mutations at all of the reported N-terminal phosphorylation sites (p53N-term), all of the C-terminal phosphorylation sites (p53C-term), or all of the phosphorylation sites together (p53N/C-term). Each of these mutant proteins retained transcriptional transactivation functions, indicating that phosphorylation is not essential for this activity of p53, although a subtle contribution of the C-terminal phosphorylation sites to the activation of expression of the endogenous p21Waf1/Cip1-encoding gene was detected. Mutation of the phosphorylation sites to alanine did not affect the sensitivity of p53 to binding to or degradation by Mdm2, although alteration of residues 15 and 37 to aspartic acid, which could mimic phosphorylation, resulted in a slight resistance to Mdm2-mediated degradation, consistent with recent reports that phosphorylation at these sites inhibits the p53-Mdm2 interaction. However, expression of the phosphorylation site mutant proteins in both wild-type p53-expressing and p53-null lines showed that all of the mutant proteins retained the ability to be stabilized following DNA damage. This indicates that phosphorylation is not essential for DNA damage-induced stabilization of p53, although phosphorylation could clearly contribute to p53 stabilization under some conditions.

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Wienzek, Sandra, Judith Roth, and Matthias Dobbelstein. "E1B 55-Kilodalton Oncoproteins of Adenovirus Types 5 and 12 Inactivate and Relocalize p53, but Not p51 or p73, and Cooperate with E4orf6 Proteins To Destabilize p53." Journal of Virology 74, no. 1 (January 1, 2000): 193–202. http://dx.doi.org/10.1128/jvi.74.1.193-202.2000.

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ABSTRACT The p53 tumor suppressor protein represents a target for viral and cellular oncoproteins, including adenovirus gene products. Recently, it was discovered that several proteins with structural and functional homologies to p53 exist in human cells. Two of them were termed p51 and p73. We have shown previously that the E1B 55-kDa protein (E1B-55 kDa) of adenovirus type 5 (Ad5) binds and inactivates p53 but not p73. Further, p53 is rapidly degraded in the presence of E1B-55 kDa and the E4orf6 protein of this virus. Here, it is demonstrated that p51 does not detectably associate with E1B-55 kDa. While p53 is relocalized to the cytoplasm by E1B-55 kDa, p51's location is unaffected. Finally, p51 retains its full transcriptional activity in the presence of E1B-55 kDa. Apparently, p51 does not represent a target of Ad5 E1B-55 kDa, suggesting that the functions of p51 are distinct from p53-like tumor suppression. E1B-55 kDa from highly oncogenic adenovirus type 12 (Ad12) was previously shown to surpass the oncogenic activity of Ad5 E1B-55 kDa in various assay systems, raising the possibility that Ad12 E1B-55 kDa might target a broader range of p53-like proteins. However, we show here that Ad12 E1B-55 kDa also inhibits p53's transcriptional activity without measurably affecting p73 or p51. Moderate inhibition of p51's transcriptional activity was observed in the presence of the E4orf6 proteins from Ad5 and Ad12. p53 and Ad12-E1B-55 kDa colocalize in the nucleus and also in cytoplasmic clusters when transiently coexpressed. Finally, E1B-55 kDa and E4orf6 of Ad12 mediate rapid degradation of p53 with an efficiency comparable to that of the Ad5 proteins in human and rodent cells. Our results suggest that E1B-55 kDa of either virus type has similar effects on p53 but does not affect p73 and p51.

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Rocha, Sonia, Anthea M. Martin, David W. Meek, and Neil D. Perkins. "p53 Represses Cyclin D1 Transcription through Down Regulation of Bcl-3 and Inducing Increased Association of the p52 NF-κB Subunit with Histone Deacetylase 1." Molecular and Cellular Biology 23, no. 13 (July 1, 2003): 4713–27. http://dx.doi.org/10.1128/mcb.23.13.4713-4727.2003.

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ABSTRACT The p53 and NF-κB transcription factor families are important, multifunctional regulators of the cellular response to stress. Here we have investigated the regulatory mechanisms controlling p53-dependent cell cycle arrest and cross talk with NF-κB. Upon induction of p53 in H1299 or U-2 OS cells, we observed specific repression of cyclin D1 promoter activity, correlating with a decrease in cyclin D1 protein and mRNA levels. This repression was dependent on the proximal NF-κB binding site of the cyclin D1 promoter, which has been shown to bind the p52 NF-κB subunit. p53 inhibited the expression of Bcl-3 protein, a member of the IκB family that functions as a transcriptional coactivator for p52 NF-κB and also reduced p52/Bcl-3 complex levels. Concomitant with this, p53 induced a significant increase in the association of p52 and histone deacetylase 1 (HDAC1). Importantly, p53-mediated suppression of the cyclin D1 promoter was reversed by coexpression of Bcl-3 and inhibition of p52 or deacetylase activity. p53 therefore induces a transcriptional switch in which p52/Bcl-3 activator complexes are replaced by p52/HDAC1 repressor complexes, resulting in active repression of cyclin D1 transcription. These results reveal a unique mechanism by which p53 regulates NF-κB function and cell cycle progression.

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Terrier, Olivier, Virginie Marcel, Gaëlle Cartet, David P. Lane, Bruno Lina, Manuel Rosa-Calatrava, and Jean-Christophe Bourdon. "Influenza A Viruses Control Expression of Proviral Human p53 Isoforms p53β and Δ133p53α." Journal of Virology 86, no. 16 (May 30, 2012): 8452–60. http://dx.doi.org/10.1128/jvi.07143-11.

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Previous studies have described the role of p53 isoforms, including p53β and Δ133p53α, in the modulation of the activity of full-length p53, which regulates cell fate. In the context of influenza virus infection, an interplay between influenza viruses and p53 has been described, with p53 being involved in the antiviral response. However, the role of physiological p53 isoforms has never been explored in this context. Here, we demonstrate that p53 isoforms play a role in influenza A virus infection by using silencing and transient expression strategies in human lung epithelial cells. In addition, with the help of a panel of different influenza viruses from different subtypes, we also show that infection differentially regulates the expressions of p53β and Δ133p53α. Altogether, our results highlight the role of p53 isoforms in the viral cycle of influenza A viruses, with p53β and Δ133p53α acting as regulators of viral production in a p53-dependent manner.

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Ikawa, Shuntaro, Masuo Obinata, and Yoji Ikawa. "Human p53-p51 (p53-Related) Fusion Protein: A PotentBAXTransactivator." Japanese Journal of Cancer Research 90, no. 6 (June 1999): 596–99. http://dx.doi.org/10.1111/j.1349-7006.1999.tb00788.x.

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Fine, Robert L., Yuehua Mao, Richard Dinnen, Ramon V. Rosal, Anthony Raffo, Uri Hochfeld, Patrick Senatus, et al. "C-Terminal p53 Palindromic Tetrapeptide Restores Full Apoptotic Function to Mutant p53 Cancer Cells In Vitro and In Vivo." Biomedicines 11, no. 1 (January 5, 2023): 137. http://dx.doi.org/10.3390/biomedicines11010137.

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We previously demonstrated that a synthetic monomer peptide derived from the C-terminus of p53 (aa 361–382) induced preferential apoptosis in mutant p53 malignant cells, but not normal cells. The major problem with the peptide was its short half-life (half-life < 10 min.) due to a random coil topology found in 3D proton NMR spectroscopy studies. To induce secondary/tertiary structures to produce more stability, we developed a peptide modelled after the tetrameric structure of p53 essential for activation of target genes. Starting with the above monomer peptide (aa 361–382), we added the nuclear localization sequence of p53 (aa 353–360) and the end of the C-terminal sequence (aa 383–393), resulting in a monomer spanning aa 353–393. Four monomers were linked by glycine to maximize flexibility and in a palindromic order that mimics p53 tetramer formation with four orthogonal alpha helices, which is required for p53 transactivation of target genes. This is now known as the 4 repeat-palindromic-p53 peptide or (4R-Pal-p53p). We explored two methods for testing the activity of the palindromic tetrapeptide: (1) exogenous peptide with a truncated antennapedia carrier (Ant) and (2) a doxycycline (Dox) inducer for endogenous expression. The exogenous peptide, 4R-Pal-p53p-Ant, contained a His tag at the N-terminal and a truncated 17aa Ant at the C-terminal. Exposure of human breast cancer MB-468 cells and human skin squamous cell cancer cells (both with mutant p53, 273 Arg->His) with purified peptide at 7 µM and 15 µM produced 52% and 75%, cell death, respectively. Comparatively, the monomeric p53 C-terminal peptide-Ant (aa 361–382, termed p53p-Ant), at 15 µM and 30 µM induced 15% and 24% cell death, respectively. Compared to the p53p-Ant, the exogenous 4R-pal-p53p-Ant was over five-fold more potent for inducing apoptosis at an equimolar concentration (15 µM). Endogenous 4R-Pal-p53p expression (without Ant), induced by Dox, resulted in 43% cell death in an engineered MB468 breast cancer stable cell line, while endogenous p53 C-terminal monomeric peptide expression produced no cell death due to rapid peptide degradation. The mechanism of apoptosis from 4R-Pal-p53p involved the extrinsic and intrinsic pathways (FAS, caspase-8, Bax, PUMA) for apoptosis, as well as increasing reactive oxygen species (ROS). All three death pathways were induced from transcriptional/translational activation of pro-apoptotic genes. Additionally, mRNA of p53 target genes (Bax and Fas) increased 14-fold and 18-fold, respectively, implying that the 4R-Pal-p53p restored full apoptotic potential to mutant p53. Monomeric p53p only increased Fas expression without a transcriptional or translational increase in Fas, and other genes and human marrow stem cell studies revealed no toxicity to normal stem cells for granulocytes, erythrocytes, monocytes, and macrophages (CFU-GEMM). Additionally, the peptide specifically targeted pre-malignant and malignant cells with mutant p53 and was not toxic to normal cells with basal levels of WT p53.

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Chen, Jing, Dadong Zhang, Xiaodi Qin, Kouros Owzar, Jennifer J. McCann, and Michael B. Kastan. "DNA-Damage-Induced Alternative Splicing of p53." Cancers 13, no. 2 (January 12, 2021): 251. http://dx.doi.org/10.3390/cancers13020251.

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Cellular responses to DNA damage and other stresses are important determinants of mutagenesis and impact the development of a wide range of human diseases. TP53 is highly mutated in human cancers and plays an essential role in stress responses and cell fate determination. A central dogma of p53 induction after DNA damage has been that the induction results from a transient increase in the half-life of the p53 protein. Our laboratory recently demonstrated that this long-standing paradigm is an incomplete picture of p53 regulation by uncovering a critical role for protein translational regulation in p53 induction after DNA damage. These investigations led to the discovery of a DNA-damage-induced alternative splicing (AS) pathway that affects p53 and other gene products. The damage-induced AS of p53 pre-mRNA generates the beta isoform of p53 (p53β) RNA and protein, which is specifically required for the induction of cellular senescence markers after ionizing irradiation (IR). In an attempt to elucidate the mechanisms behind the differential regulation and apparent functional divergence between full-length (FL) p53 and the p53β isoform (apoptosis versus senescence, respectively), we identified the differential transcriptome and protein interactome between these two proteins that may result from the unique 10-amino-acid tail in p53β protein.

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Steffens Reinhardt, Luiza, Kira Groen, Brianna C. Morten, Jean-Christophe Bourdon, and Kelly A. Avery-Kiejda. "Cytoplasmic p53β Isoforms Are Associated with Worse Disease-Free Survival in Breast Cancer." International Journal of Molecular Sciences 23, no. 12 (June 15, 2022): 6670. http://dx.doi.org/10.3390/ijms23126670.

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TP53 mutations are associated with tumour progression, resistance to therapy and poor prognosis. However, in breast cancer, TP53′s overall mutation frequency is lower than expected (~25%), suggesting that other mechanisms may be responsible for the disruption of this critical tumour suppressor. p53 isoforms are known to enhance or disrupt p53 pathway activity in cell- and context-specific manners. Our previous study revealed that p53 isoform mRNA expression correlates with clinicopathological features and survival in breast cancer and may account for the dysregulation of the p53 pathway in the absence of TP53 mutations. Hence, in this study, the protein expression of p53 isoforms, transactivation domain p53 (TAp53), p53β, Δ40p53, Δ133p53 and Δ160p53 was analysed using immunohistochemistry in a cohort of invasive ductal carcinomas (n = 108). p53 isoforms presented distinct cellular localisation, with some isoforms being expressed in tumour cells and others in infiltrating immune cells. Moreover, high levels of p53β, most likely to be N-terminally truncated β variants, were significantly associated with worse disease-free survival, especially in tumours with wild-type TP53. To the best of our knowledge, this is the first study that analysed the endogenous protein levels of p53 isoforms in a breast cancer cohort. Our findings suggest that p53β may be a useful prognostic marker.

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Ohtani, Shoichiro, Shunsuke Kagawa, Yasuhisa Tango, Tatsuo Umeoka, Naoyuki Tokunaga, Yousuke Tsunemitsu, Jack A. Roth, Yoichi Taya, Noriaki Tanaka, and Toshiyoshi Fujiwara. "Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo." Molecular Cancer Therapeutics 3, no. 1 (January 1, 2004): 93–100. http://dx.doi.org/10.1158/1535-7163.93.3.1.

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Abstract To analyze the mechanism of the antitumor effect of an adenoviral vector expressing the p53 tumor suppressor (Ad-p53) in vivo, we quantitatively assessed p53-targeted gene expression and visualized transcriptional activity of p53 in tumors in nude mice treated with Ad-p53. Human lung cancer (H1299) xenografts established in nude mice were treated by intratumoral administration of Ad-p53. The levels of expression of exogenous p53 and p53-targeted genes p21, MDM2, Noxa, and p53AIP1 were quantified by real-time reverse transcription-PCR (RT-PCR) and induction of apoptosis was observed histochemically on days 1–3, 7, and 14 after treatment. Expression of mRNA of exogenous p53 and p53-targeted genes (except p53AIP1) was at its maximum 1 day after Ad-p53 treatment and then decreased rapidly; apoptosis was evident in situ 2–3 days after treatment. We developed a noninvasive and simple method for monitoring the transcriptional activity of exogenous p53 following intratumoral administration of Ad-p53 in nude mice. We established H1299 cells that express the green fluorescent protein (GFP) reporter gene under the control of p53-responsive p21 promoter (i.e., the p53R-GFP reporter system). Xenografts of these cells in nude mice were treated by intratumoral administration of Ad-p53, and the transcriptional activity of exogenous p53 could be visualized as intratumoral GFP expression in real time by 3-CCD camera. Expression of GFP was maximal 3 days after treatment and decreased remarkably by 7 days after treatment. We demonstrated that Ad-p53 treatment rapidly induced p53-targeted genes and apoptosis in tumors and succeeded in visualizing p53 transcriptional activity in vivo. We also found that Ad-p53 infection induced phosphorylation of p53 at Ser46 in p53-sensitive H1299 cells in vitro but not in p53-resistant H226Br cells, suggesting that phosphorylation of Ser46 is involved in p53-dependent apoptosis. Our data indicate that quantitative analysis of p53-targeted gene expression by real-time quantitative RT-PCR and visualization of p53 transcriptional activity in fresh xenografts by using the p53R-GFP reporter system may be useful in assessing the mechanisms of the antitumor effects of Ad-p53 and novel therapeutic approaches.

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Matsumoto, Akinobu, Shoichiro Takeishi, and Keiichi I. Nakayama. "p57 regulates T-cell development and prevents lymphomagenesis by balancing p53 activity and pre-TCR signaling." Blood 123, no. 22 (May 29, 2014): 3429–39. http://dx.doi.org/10.1182/blood-2013-10-532390.

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Key PointsAblation of p57 in T cells blocks differentiation at an early developmental stage as a result of excessive activation of E2F. Additional ablation of E2F1 or p53 normalizes p57-deficiency phenotypes, but loss of both p57 and p53 eventually results in thymic lymphoma.

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Ko, Christine J., Peggy Myung, David J. Leffell, and Jean-Christophe Bourdon. "Cutaneous immunohistochemical staining pattern of p53β isoforms." Journal of Clinical Pathology 71, no. 12 (October 10, 2018): 1120–22. http://dx.doi.org/10.1136/jclinpath-2018-205098.

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p53 is considered the guardian of the genome and as such has numerous functions. The TP53 gene is the most commonly mutated gene in cancer, and yet the exact biological significance of such mutations remains unclear. There are at least 12 different isoforms of p53, and the complexity of the p53 pathway may be in part related to these isoforms. Prior research has often not teased out what isoforms of p53 are being studied, and there is evidence in the literature that p53 isoforms are expressed differently. In this paper, we document the staining pattern of p53β isoforms in the skin and correlate it with mutational status in a subgroup of squamous proliferations of the skin. p53β isoforms are present in the cytoplasm of the differentiated layer of the epidermis and hair follicles (granular layer, infundibular and isthmus–catagen). p53β isoforms are diffusely expressed within the cytoplasm of well-differentiated squamous tumours with tetramerisation (C-terminal) domain mutations in TP53. Our results lend support to p53β isoforms being a marker of differentiation in keratinocytes.

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Muller, Patricia A. J., Karen H. Vousden, and Jim C. Norman. "p53 and its mutants in tumor cell migration and invasion." Journal of Cell Biology 192, no. 2 (January 24, 2011): 209–18. http://dx.doi.org/10.1083/jcb.201009059.

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In about half of all human cancers, the tumor suppressor p53 protein is either lost or mutated, frequently resulting in the expression of a transcriptionally inactive mutant p53 protein. Loss of p53 function is well known to influence cell cycle checkpoint controls and apoptosis. But it is now clear that p53 regulates other key stages of metastatic progression, such as cell migration and invasion. Moreover, recent data suggests that expression of mutant p53 is not the equivalent of p53 loss, and that mutant p53s can acquire new functions to drive cell migration, invasion, and metastasis, in part by interfering with p63 function.

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Gasparro, Francis P. "p53, p54, PUVA, and counting." Journal of the American Academy of Dermatology 41, no. 5 (November 1999): 800–801. http://dx.doi.org/10.1016/s0190-9622(99)70018-6.

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Nakade, Koji, Hong Zheng, Gitali Ganguli, Gilles Buchwalter, Christian Gross, and Bohdan Wasylyk. "The Tumor Suppressor p53 Inhibits Net, an Effector of Ras/Extracellular Signal-Regulated Kinase Signaling." Molecular and Cellular Biology 24, no. 3 (February 1, 2004): 1132–42. http://dx.doi.org/10.1128/mcb.24.3.1132-1142.2004.

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ABSTRACT The tumor suppressor function of p53 is linked to its ability to repress gene expression, but the mechanisms of specific gene repression are poorly understood. We report that wild-type p53 inhibits an effector of the Ras oncogene/mitogen-activated protein (MAP) kinase pathway, the transcription factor Net. Tumor-associated mutant p53s are less efficient inhibitors. p53 inhibits by preventing phosphorylation of Net by MAP kinases. Loss of p53 in vivo leads to increased Net phosphorylation in response to wound healing and UV irradiation of skin. Our results show that p53 can repress specific gene expression by inhibiting Net, a factor implicated in cell cycle entry.

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Valbuena, Alberto, Francisco M. Vega, Sandra Blanco, and Pedro A. Lazo. "p53 Downregulates Its Activating Vaccinia-Related Kinase 1, Forming a New Autoregulatory Loop." Molecular and Cellular Biology 26, no. 13 (July 1, 2006): 4782–93. http://dx.doi.org/10.1128/mcb.00069-06.

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ABSTRACT The stable accumulation of p53 is detrimental to the cell because it blocks cell growth and division. Therefore, increases in p53 levels are tightly regulated, mainly by its transcriptional target, mdm2, that downregulates p53. Elucidation of new signaling pathways requires the characterization of the members and the nature of their connection. Vaccinia-related kinase 1 (VRK1) contributes to p53 stabilization by partly interfering with its mdm2-mediated degradation, among other mechanisms; therefore, it is likely that some form of autoregulation between VRK1 and p53 must occur. We report here the identification of an autoregulatory loop between p53 and its stabilizing VRK1. There is an inverse correlation between VRK1 and p53 levels in cell lines, and induction of p53 by UV light downregulates VRK1 in fibroblasts. As the amount of p53 protein increases, there is a downregulation of the VRK1 protein level independent of its promoter. This effect is indirect but requires a transcriptionally active p53. The three most common transcriptionally inactive mutations detected in hereditary (Li-Fraumeni syndrome) and sporadic human cancer, p53(R175H), p53(R248W), and p53(R273H), as well as p53(R280K), are unable to induce downregulation of VRK1 protein. The p53 isoforms Δ40p53 and p53β, lacking the transactivation and oligomerization domains, respectively, do not downregulate VRK1. VRK1 downregulation induced by p53 is independent of mdm2 activity and proteasome-mediated degradation since it occurs in the presence of proteasome inhibitors and in mdm2-deficient cells. The degradation of VRK1 is sensitive to chloroquine, an inhibitor of the late endosome-lysosome transport, and to serine protease inhibitors of the lysosomal pathway.

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Turnham, Daniel J., Hannah Smith, and Richard W. E. Clarkson. "Suppression of Bcl3 Disrupts Viability of Breast Cancer Cells through Both p53-Dependent and p53-Independent Mechanisms via Loss of NF-κB Signalling." Biomedicines 12, no. 1 (January 10, 2024): 143. http://dx.doi.org/10.3390/biomedicines12010143.

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The NF-κB co-factor Bcl3 is a proto-oncogene that promotes breast cancer proliferation, metastasis and therapeutic resistance, yet its role in breast cancer cell survival is unclear. Here, we sought to determine the effect of Bcl3 suppression alone on breast cancer cell viability, with a view to informing future studies that aim to target Bcl3 therapeutically. Bcl3 was suppressed by siRNA in breast cancer cell lines before changes in viability, proliferation, apoptosis and senescence were examined. Bcl3 suppression significantly reduced viability and was shown to induce apoptosis in all cell lines tested, while an additional p53-dependent senescence and senescence-associated secretory phenotype was also observed in those cells with functional p53. The role of the Bcl3/NF-κB axis in this senescence response was confirmed via siRNA of the non-canonical NF-κB subunit NFKB2/p52, which resulted in increased cellular senescence and the canonical subunit NFKB1/p50, which induced the senescence-associated secretory phenotype. An analysis of clinical data showed a correlation between reduced relapse-free survival in patients that expressed high levels of Bcl3 and carried a p53 mutation. Together, these data demonstrate a dual role for Bcl3/NF-κB in the maintenance of breast cancer cell viability and suggests that targeting Bcl3 may be more beneficial to patients with tumours that lack functional p53.

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Roth, Judith, and Matthias Dobbelstein. "Failure of viral oncoproteins to target the p53-homologue p51A." Journal of General Virology 80, no. 12 (December 1, 1999): 3251–55. http://dx.doi.org/10.1099/0022-1317-80-12-3251.

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The p51/p63/KET proteins were identified based on their strong homology to the tumour suppressor p53 and a related set of proteins termed p73. All these protein species were shown to activate transcription from at least some p53-responsive promoters. To evaluate a possible role of the transcriptionally active splicing variant p51A/p63γ in tumour suppression, we determined whether viral oncoproteins that inactivate p53 might also target p51A. Neither the large T-antigen of simian vacuolating virus 40 (SV40) nor the E6 protein from human papillomavirus type 18 were found to inhibit p51A-mediated transcription, whereas they strongly suppress the activity of p53. Further, SV40 T-antigen directly interacts with p53 but not detectably with p51A. Finally, a cytoplasmic mutant (K128A) of SV40 T-antigen relocalizes p53 from the nucleus to the cytoplasm, but p51A remains in the nucleus when coexpressed with cytoplasmic T-antigen. These results strongly suggest that the inhibitory effect of these viral oncoproteins is specific for p53 and does not measurably affect p51A. Thus, unlike p53, p51A does not appear to be a necessary target in virus-induced cell transformation and may not exert a role comparable to p53 in tumour suppression.

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Bosch, F. X., N. Homann, C. Conradt, A. Dietz, and R. Erber. "p53-Mutationen/ p53-Proteinüberexpression." HNO 47, no. 9 (October 1, 1999): 833–48. http://dx.doi.org/10.1007/s001060050470.

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Zhang, Yuewei. "Trans-catheter arterial p53-gene-embolization using gelatin sponge particles in treatment of patients with advanced hepatocellular carcinoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15024-e15024. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15024.

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e15024 Background: Treatment options for advanced hepatocellular carcinoma (HCC) are limited due to patients’ poor condition, and resistance to both chemo- and radio-therapy. Trans-catheter embolization (TAE) or Trans-catheter chemo-embolization (TACE) is the most widely used locoregional treatment for advanced HCC. But no solid evidences support the beneficial effect of the chemotherapy in TACE. Many advanced HCC patients also can’t tolerate the locoregional chemotherapy. The p53 gene has multiple anticancer functions and does not have any of the immune-inhibitory effects of chemo- or radio-therapy. The objectives of this study are to investigate TAE plus recombinant adenoviral human p53 gene (rAd-p53) in treatment of advanced HCC. Methods: Fifty-eight patients with advanced, unresectable HCC were randomly to two groups: TAE plus p53 group (TAE-p53G), or TAE group (TAEG). The study patients included 56 males and 2 females with an average age of 62.5 (53-89) years old and with Child-Pugh score A or B (42 or 16, respectively). The patients received 3 times of TAE plus rAd-p53 for TAE-p53G or TAE only for TAEG, once in a month for 3 months. The TAE materials consist of gelatin sponge particles (GSP) alone or plus 2-4 x 1012viral particles of rAd-p53, mixed into 30 ml suspension. The study endpoints included response rate, one-year survival, liver function, and adverse effects. Results: After 3-5 days of the first treatment, CT scan showed deceased tumor density in all the study cases. At 6 months after the first treatment, based on the RECIST standard, 31.0% (9/29) and 51.7% (15/29) patients in TAE-p53G achieved a complete response (CR) and partial response (PR), respectively, versus 17.2% (5/29) and 37.9% (11/29) of CR and PR in TAEG, respectively. One-year survival rates were 79.4% and 60.7% with median survival time of 11.7 and 8.3 months for TAE-p53G and TAEG, respectively. There are no significant changes of liver functions in both groups after treatment. Mild or median fever was observed in all the patients in TAE-p53G. No serious adverse events or complications observed. Conclusions: TAE using GSPs plus rAd-p53 is effective and safe treatments for advanced HCC.

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Samad, A., and R. B. Carroll. "The tumor suppressor p53 is bound to RNA by a stable covalent linkage." Molecular and Cellular Biology 11, no. 3 (March 1991): 1598–606. http://dx.doi.org/10.1128/mcb.11.3.1598-1606.1991.

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We have previously shown that the carboxyl-terminal tryptic peptide of the tumor suppressor p53 coeluted from reverse-phase high-performance liquid chromatography (HPLC) with ribonucleotides, suggesting the possible linkage of RNA to p53. In this report, we establish that p53 is covalently linked to RNA, using biochemical criteria at the levels of both tryptic peptide and intact protein: the electrophoretic properties of a tryptic peptide containing phosphorylated Ser-389 and the HPLC chromatographic properties of p53 depend on the linked RNA, p53, purified through urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis and HPLC, copurifies with RNA, and Ser-389 liberates ribonucleotides upon RNase or alkali treatment. Wild-type and mutant p53s from both simian virus 40 (SV40)-transformed and SV40-nontransformed cells are RNA linked, indicating that RNA linkage may be a general property of p53. The RNA is labeled in vivo with 3H-uridine and in vitro by RNA ligase, suggesting that the RNA is bound by a 5' linkage. The RNA is a long-lived, integral component of p53 rather than a transient reaction intermediate. RNA linkage occurs at an evolutionarily conserved site on p53. We propose that RNA-linked p53 is a major biologically active form of p53 and that its interaction with RNA-linked SV40 T antigen reflects a role in RNA metabolism.

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Samad, A., and R. B. Carroll. "The tumor suppressor p53 is bound to RNA by a stable covalent linkage." Molecular and Cellular Biology 11, no. 3 (March 1991): 1598–606. http://dx.doi.org/10.1128/mcb.11.3.1598.

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We have previously shown that the carboxyl-terminal tryptic peptide of the tumor suppressor p53 coeluted from reverse-phase high-performance liquid chromatography (HPLC) with ribonucleotides, suggesting the possible linkage of RNA to p53. In this report, we establish that p53 is covalently linked to RNA, using biochemical criteria at the levels of both tryptic peptide and intact protein: the electrophoretic properties of a tryptic peptide containing phosphorylated Ser-389 and the HPLC chromatographic properties of p53 depend on the linked RNA, p53, purified through urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis and HPLC, copurifies with RNA, and Ser-389 liberates ribonucleotides upon RNase or alkali treatment. Wild-type and mutant p53s from both simian virus 40 (SV40)-transformed and SV40-nontransformed cells are RNA linked, indicating that RNA linkage may be a general property of p53. The RNA is labeled in vivo with 3H-uridine and in vitro by RNA ligase, suggesting that the RNA is bound by a 5' linkage. The RNA is a long-lived, integral component of p53 rather than a transient reaction intermediate. RNA linkage occurs at an evolutionarily conserved site on p53. We propose that RNA-linked p53 is a major biologically active form of p53 and that its interaction with RNA-linked SV40 T antigen reflects a role in RNA metabolism.

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Legagneux, V., P. Bouvet, F. Omilli, S. Chevalier, and H. B. Osborne. "Identification of RNA-binding proteins specific to Xenopus Eg maternal mRNAs: association with the portion of Eg2 mRNA that promotes deadenylation in embryos." Development 116, no. 4 (December 1, 1992): 1193–202. http://dx.doi.org/10.1242/dev.116.4.1193.

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Maternal Xenopus Eg mRNAs have been previously identified as transcripts that are specifically deadenylated after fertilization and degraded after the mid blastula transition. Destabilizing cis sequences were previously localised in the 3′ untranslated region of Eg2 mRNA. In order to characterize possible trans-acting factors which are involved in the post-transcriptional regulation of Eg mRNAs, gel-shift and u.v. cross-linking experiments were performed, which allowed the identification of a p53-p55 RNA-binding protein doublet specific for the 3′ untranslated regions of Eg mRNAs. These p53-p55 proteins do not bind to the 3′ untranslated regions of either ornithine decarboxylase or phosphatase 2Ac mRNAs, which remain polyadenylated in embryos. These novel RNA-binding proteins are distinct from the cytoplasmic polyadenylation element-binding protein that controls the polyadenylation of maternal mRNAs in maturing Xenopus oocytes, and from previously identified thermoresistant RNA-binding proteins present in oocyte mRNP storage particles. The p53-p55 bind a portion of the Eg2 mRNA 3′ untranslated region, distinct from the previously identified destabilizing region, that is able to confer the postfertilization deadenylation of CAT-coding chimeric mRNAs. This suggests that the p53-p55 RNA-binding proteins are good candidates for trans-acting factors involved in the deadenylation of Eg mRNAs in Xenopus embryos.

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López-Amado, Manuel, Tomás García-Caballero, Ascensión Lozano-Ramírez, and Torcuato Labella-Caballero. "Human papillomavirus and p53 oncoprotein in verrucous carcinoma of the larynx." Journal of Laryngology & Otology 110, no. 8 (August 1996): 742–47. http://dx.doi.org/10.1017/s0022215100134851.

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AbstractThe incidence of p53 antigen and human papillomavirus (HPV) expression in archival formalin-fixed, paraffin-embedded tissue sections from verrucous carcinoma of the larynx was determined using immunohistochemistry.The p53 oncoprotein was detected in four of 10 tissue samples (40 per cent). The same number of tumours had HPV antigen, and three cases had both p53 oncoprotein and HPV antigen. All positive cases were from heavy smokers and drinkers.After surgical treatment, no tumour recurrence was present in our series. Four patients developed a second head and neck neoplasm and death occurred in three. Three of the patients with second tumour had p53 positive immunoreactivity and two had p13 and HPV expression.Verrucous carcinoma of the larynx presented with overexpression of p53 antigen in a similar percentage to other head and neck cancers. The p53 immunohistochemical determination is well correlated with HPV detection and could have prognostic value in these tumours, but no statistical evidence was present.

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Pan, Yongping, and Ruth Nussinov. "p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions." Journal of Physical Chemistry B 112, no. 21 (May 2008): 6716–24. http://dx.doi.org/10.1021/jp800680w.

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Porubiaková, Otília, Natália Bohálová, Alberto Inga, Natália Vadovičová, Jan Coufal, Miroslav Fojta, and Václav Brázda. "The Influence of Quadruplex Structure in Proximity to P53 Target Sequences on the Transactivation Potential of P53 Alpha Isoforms." International Journal of Molecular Sciences 21, no. 1 (December 24, 2019): 127. http://dx.doi.org/10.3390/ijms21010127.

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p53 is one of the most studied tumor suppressor proteins that plays an important role in basic biological processes including cell cycle, DNA damage response, apoptosis, and senescence. The human TP53 gene contains alternative promoters that produce N-terminally truncated proteins and can produce several isoforms due to alternative splicing. p53 function is realized by binding to a specific DNA response element (RE), resulting in the transactivation of target genes. Here, we evaluated the influence of quadruplex DNA structure on the transactivation potential of full-length and N-terminal truncated p53α isoforms in a panel of S. cerevisiae luciferase reporter strains. Our results show that a G-quadruplex prone sequence is not sufficient for transcription activation by p53α isoforms, but the presence of this feature in proximity to a p53 RE leads to a significant reduction of transcriptional activity and changes the dynamics between co-expressed p53α isoforms.

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Brownlee, Noel A., L. Allen Perkins, Will Stewart, Beth Jackle, Mark J. Pettenati, Patrick P. Koty, Samy S. Iskandar, and A. Julian Garvin. "Recurring Translocation (10;17) and Deletion (14q) in Clear Cell Sarcoma of the Kidney." Archives of Pathology & Laboratory Medicine 131, no. 3 (March 1, 2007): 446–51. http://dx.doi.org/10.5858/2007-131-446-rtadqi.

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Abstract Context.—Clear cell sarcoma of the kidney (CCSK) is a prognostically unfavorable renal neoplasm of childhood. Previous cytogenetic studies of CCSK have reported balanced translocations t(10;17)(q22;p13) and t(10;17)(q11; p12). Although the tumor suppressor gene p53 is located at the chromosome 17p13 breakpoint, p53 abnormalities are rarely present in these tumors. Objective.—To identify cytogenetic abnormalities in CCSK and correlate these findings with other clinicopathologic parameters. Design.—A retrospective review of CCSK patients from 1990 to 2005 was conducted at our medical center. We performed clinical and histologic review, p53 immunohistochemical and classic cytogenetics (or ploidy analysis), and p53 fluorescence in situ hybridization analyses. Results.—Five male patients (age range, 6 months to 4 years) were identified with cytogenetic abnormalities. Of 3 cytogenetically informative cases, one revealed a clonal balanced translocation t(10;17)(q22;p13) and an interstitial deletion of chromosome 14, del(14)(q24.1q31.1), and the other 2 patients had normal karyotypes. Fluorescence in situ hybridization for p53 in the t(10;17) case revealed no deletion. Immunohistochemical evaluation of p53 demonstrated lack of nuclear protein accumulation in all cases. Conclusions.—Together with the published literature, our results indicate that translocation (10;17) and interstitial deletions of chromosome 14q are recurring cytogenetic lesions in CCSK. To date, 3 cases of CCSK or “sarcomatoid Wilms tumors” have been reported to exhibit t(10;17). One previously reported case of CCSK contained deletion 14q. Results of p53 immunohistochemistry and/or p53 fluorescence in situ hybridization in this report suggest lack of mutations or deletions of this tumor suppressor in these CCSK cases. The t(10;17) breakpoint and deletion of chromosome 14q24 suggest that other genes are involved in tumor pathogenesis.

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Choi, Geon. "Cancer and p53." Journal of Clinical Otolaryngology Head and Neck Surgery 7, no. 1 (May 1996): 19–31. http://dx.doi.org/10.35420/jcohns.1996.7.1.19.

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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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Bourdon, JC. "p53 isoforms change p53 paradigm." Molecular & Cellular Oncology 1, no. 4 (December 8, 2014): e969136. http://dx.doi.org/10.4161/23723548.2014.969136.

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Lei, Jiangtao, Xuanyao Li, Mengqiang Cai, Tianjing Guo, Dongdong Lin, Xiaohua Deng, and Yin Li. "Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L." International Journal of Molecular Sciences 23, no. 17 (September 3, 2022): 10100. http://dx.doi.org/10.3390/ijms231710100.

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Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser β-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249–267 and 268–282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants.

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McKenna, Declan J., Simon S. McDade, Daksha Patel, and Dennis J. McCance. "MicroRNA 203 Expression in Keratinocytes Is Dependent on Regulation of p53 Levels by E6." Journal of Virology 84, no. 20 (August 11, 2010): 10644–52. http://dx.doi.org/10.1128/jvi.00703-10.

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ABSTRACT A screen of microRNA (miRNA) expression following differentiation in human foreskin keratinocytes (HFKs) identified changes in several miRNAs, including miRNA 203 (miR-203), which has previously been shown to play an important role in epithelial cell biology by regulating p63 levels. We investigated how expression of human papillomavirus type 16 (HPV16) oncoproteins E6 and E7 affected miR-203 expression during proliferation and differentiation of HFKs. We demonstrated that miR-203 expression is reduced in HFKs where p53 function is compromised, either by the viral oncoprotein E6 or by knockout of p53 using short hairpin RNAs (p53i). We show that the induction of miR-203 observed during calcium-induced differentiation of HFKs is significantly reduced in HFKs expressing E6 and in p53i HFKs. Induction of miR-203 in response to DNA damage is also reduced in the absence of p53. We report that proliferation of HFKs is dependent on the level of miR-203 expression and that overexpression of miR-203 can reduce overproliferation in E6/E7-expressing and p53i HFKs. In summary, these results indicate that expression of miR-203 is dependent on p53, which may explain how expression of HPV16 E6 can disrupt the balance between proliferation and differentiation, as well as the response to DNA damage, in keratinocytes.

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Cui, Yu-Xin, Alan Kerby, Fiona Kate Elizabeth McDuff, Hongtao Ye, and Suzanne Dawn Turner. "NPM-ALK inhibits the p53 tumor suppressor pathway in an MDM2 and JNK-dependent manner." Blood 113, no. 21 (May 21, 2009): 5217–27. http://dx.doi.org/10.1182/blood-2008-06-160168.

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Abstract Anaplastic large cell lymphoma (ALCL) is characterized by the presence of the t(2;5)(p23;q35) generating the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, a hyperactive kinase with transforming properties. Among these properties is the ability to regulate activity of the p53 tumor suppressor protein. In many human cancers, p53 is inactivated by mutation or other means, in some cases as a result of up-regulation of the negative regulator MDM2. However, the majority of ALK-expressing ALCL carry wild-type p53 and do not over express MDM2. We demonstrate a novel p53-dependent pathogenetic mechanism in ALK-expressing lymphoma. We confirm previously published reports of NPM-ALK–induced activation of the phosphoinositide (PI) 3-kinase and Jun N-terminal kinase (JNK) stress-activated protein (SAP) kinase proteins, but in this study demonstrate a role for these in the regulation of p53 activity in an intricate signaling system. Specifically, constitutive ALK signaling leads to the functional inactivation and/or degradation of p53 in JNK and MDM2 dependent manners. We also show nuclear exclusion of p53 in a PI 3-kinase–dependent manner. Furthermore, we demonstrate that reactivation of p53 in ALK-expressing cells as a result of pharmacologic inhibition of JNK, PI 3-kinase, and/or MDM2 activities results in the induction of apoptosis suggesting a novel therapeutic modality.

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Fujita, Kaori. "p53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions." International Journal of Molecular Sciences 20, no. 23 (November 29, 2019): 6023. http://dx.doi.org/10.3390/ijms20236023.

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Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases.

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Whitesell, Luke, Patrick D. Sutphin, Elizabeth J. Pulcini, Jesse D. Martinez, and Paul H. Cook. "The Physical Association of Multiple Molecular Chaperone Proteins with Mutant p53 Is Altered by Geldanamycin, an hsp90-Binding Agent." Molecular and Cellular Biology 18, no. 3 (March 1, 1998): 1517–24. http://dx.doi.org/10.1128/mcb.18.3.1517.

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ABSTRACT Wild-type p53 is a short-lived protein which turns over very rapidly via selective proteolysis in the ubiquitin-proteasome pathway. Most p53 mutations, however, encode for protein products which display markedly increased intracellular levels and are associated with positive tumor-promoting activity. The mechanism by which mutation leads to impairment of ubiquitination and proteasome-mediated degradation is unknown, but it has been noted that many transforming p53 mutants are found in stable physical association with molecular chaperones of the hsp70 class. To explore a possible role for aberrant chaperone interactions in mediating the altered function of mutant p53 and its intracellular accumulation, we examined the chaperone proteins which physically associate with a temperature-sensitive murine p53 mutant. In lysate prepared from A1-5 cells grown under mutant temperature conditions, hsp70 coprecipitated with p53Val135 as previously reported by others, but in addition, other well-recognized elements of the cellular chaperone machinery, including hsp90, cyclophilin 40, and p23, were detected. Under temperature conditions favoring wild-type p53 conformation, the coprecipitation of chaperone proteins with p53 was lost in conjunction with the restoration of its transcriptional activating activity. Chaperone interactions similar to those demonstrated in A1-5 cells under mutant conditions were also detected in human breast cancer cells expressing two different hot-spot mutations. To examine the effect of directly disrupting chaperone interactions with mutant p53, we made use of geldanamycin (GA), a selective hsp90-binding agent which has been shown to alter the chaperone associations regulating the function of unliganded steroid receptors. GA treatment of cells altered heteroprotein complex formation with several different mutant p53 species. It increased p53 turnover and resulted in nuclear translocation of the protein in A1-5 cells. GA did not, however, appear to restore wild-type transcriptional activating activity to mutant p53 proteins in either A1-5 cells or human breast cancer cell lines.

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Wang, GuoZhen, and Alan R. Fersht. "Propagation of aggregated p53: Cross-reaction and coaggregation vs. seeding." Proceedings of the National Academy of Sciences 112, no. 8 (February 9, 2015): 2443–48. http://dx.doi.org/10.1073/pnas.1500262112.

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Destabilized mutant p53s coaggregate with WT p53, p63, and p73 in cancer cell lines. We found that stoichiometric amounts of aggregation-prone mutants induced only small amounts of WT p53 to coaggregate, and preformed aggregates did not significantly seed the aggregation of bulk protein. Similarly, p53 mutants trapped only small amounts of p63 and p73 into their p53 aggregates. Tetrameric full-length protein aggregated at similar rates and kinetics to isolated core domains, but there was some induced aggregation of WT by mutants in hetero-tetramers. p53 aggregation thus differs from the usual formation of amyloid fibril or prion aggregates where tiny amounts of preformed aggregate rapidly seed further aggregation. The proposed aggregation mechanism of p53 of rate-determining sequential unfolding and combination of two molecules accounts for the difference. A molecule of fast-unfolding mutant preferentially reacts with another molecule of mutant and only occasionally traps a slower unfolding WT molecule. The mutant population rapidly self-aggregates before much WT protein is depleted. Subsequently, WT protein self-aggregates at its normal rate. However, the continual production of mutant p53 in a cancer cell would gradually trap more and more WT and other proteins, accounting for the observations of coaggregates in vivo. The mechanism corresponds more to trapping by cross-reaction and coaggregation rather than classical seeding and growth.

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Graupner, Vilma, Klaus Schulze-Osthoff, Frank Essmann, and Reiner U. Jänicke. "Functional characterization of p53β and p53γ, two isoforms of the tumor suppressor p53." Cell Cycle 8, no. 8 (April 15, 2009): 1238–48. http://dx.doi.org/10.4161/cc.8.8.8251.

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Nourani, Amine, Yannick Doyon, Rhea T. Utley, Stéphane Allard, William S. Lane, and Jacques Côté. "Role of an ING1 Growth Regulator in Transcriptional Activation and Targeted Histone Acetylation by the NuA4 Complex." Molecular and Cellular Biology 21, no. 22 (November 15, 2001): 7629–40. http://dx.doi.org/10.1128/mcb.21.22.7629-7640.2001.

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ABSTRACT The yeast NuA4 complex is a histone H4 and H2A acetyltransferase involved in transcription regulation and essential for cell cycle progression. We identify here a novel subunit of the complex, Yng2p, a plant homeodomain (PHD)-finger protein homologous to human p33/ING1, which has tumor suppressor activity and is essential for p53 function. Mass spectrometry, immunoblotting, and immunoprecipitation experiments confirm the stable stoichiometric association of this protein with purified NuA4. Yeast cells harboring a deletion of theYNG2 gene show severe growth phenotype and have gene-specific transcription defects. NuA4 complex purified from the mutant strain is low in abundance and shows weak histone acetyltransferase activity. We demonstrate conservation of function by the requirement of Yng2p for p53 to function as a transcriptional activator in yeast. Accordingly, p53 interacts with NuA4 in vitro and in vivo, an interaction reminiscent of the p53-ING1 physical link in human cells. The growth defect of Δyng2 cells can be rescued by the N-terminal part of the protein, lacking the PHD-finger. While Yng2 PHD-finger is not required for p53 interaction, it is necessary for full expression of the p53-responsive gene and other NuA4 target genes. Transcriptional activation by p53 in vivo is associated with targeted NuA4-dependent histone H4 hyperacetylation, while histone H3 acetylation levels remain unchanged. These results emphasize the essential role of the NuA4 complex in the control of cell proliferation through gene-specific transcription regulation. They also suggest that regulation of mammalian cell proliferation by p53-dependent transcriptional activation functions through recruitment of an ING1-containing histone acetyltransferase complex.

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Hofseth, Lorne J., Ana I. Robles, Qin Yang, Xin W. Wang, S. Perwez Hussain, and Curtis Harris. "p53." Chest 125, no. 5 (May 2004): 83S—85S. http://dx.doi.org/10.1378/chest.125.5_suppl.83s-a.

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Wang, Ping-yuan, Jie Zhuang, and Paul M. Hwang. "p53." Current Opinion in Oncology 24, no. 1 (January 2012): 76–82. http://dx.doi.org/10.1097/cco.0b013e32834de1d8.

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Knipp, Markus, Chunmao He, and Hideaki Ogata. "P53." Nitric Oxide 31 (April 2013): S36. http://dx.doi.org/10.1016/j.niox.2013.02.055.

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Sharpless, Norman E., and Ronald A. DePinho. "p53." Cell 110, no. 1 (July 2002): 9–12. http://dx.doi.org/10.1016/s0092-8674(02)00818-8.

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Gossett, Linda. "P53." Journal of Nutrition Education and Behavior 38, no. 4 (July 2006): S36. http://dx.doi.org/10.1016/j.jneb.2006.04.060.

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Rettammel, Amy. "P53." Journal of Nutrition Education and Behavior 39, no. 4 (July 2007): S125. http://dx.doi.org/10.1016/j.jneb.2007.04.344.

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Marshall, John B., Dawn M. Miller, Aviv Ben-Meir, Helmut Schreiber, Indukumar Sonpal, Linda Patterson, Mark Salomone, and Karen Schulz. "P53." Surgery for Obesity and Related Diseases 2, no. 3 (May 2006): 327. http://dx.doi.org/10.1016/j.soard.2006.04.129.

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Ellsmere, James C., Michael A. Edwards, Ronit Grinbaum, Benjamin E. Schneider, and Daniel B. Jones. "P53." Surgery for Obesity and Related Diseases 3, no. 3 (May 2007): 317. http://dx.doi.org/10.1016/j.soard.2007.03.121.

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Kurilovich, S., V. Reshetnikov, and T. Nikitenko. "P53." European Journal of Cancer Supplements 13, no. 1 (November 2015): 30–31. http://dx.doi.org/10.1016/j.ejcsup.2015.08.054.

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Journal articles on the topic 'P53'

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