Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53

Marques, Mayra A.; Andrade, Guilherme C.; Silva, Jerson L.; Oliveira, Guilherme A. P. de

doi:10.3389/fmolb.2022.944955

Cited by 11 publications

(12 citation statements)

References 311 publications

(409 reference statements)

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“…p53 is a transcriptional factor and protector of the genome, preventing cells from undergoing malignance transformation. In the context of tumor-suppressive activities, p53 has a growing list of functionalities that goes beyond triggering apoptosis, senescence, and cell cycle arrest . The problem arises when destabilized p53 mutations hijack its tumor suppressor activities, and p53 malignancy occurs.…”

Section: Phase Separation and Transition Of The P53 Tumor Suppressor ...mentioning

confidence: 99%

“…For example, phosphorylation of FUS and TDP-43 leads to LLPS inhibition, , whereas in Tau, it is a PS inducer . The N-terminal and C-terminal flexible regions of p53 are often termed “molecular antennas”, as these segments are targets of several PTMs, but to date, there are no reports linking p53 PTMs as regulators of LLPS formation or dissolution.…”

Section: Modulators Of Phase Separation and Transitionmentioning

confidence: 99%

“…In the context of tumor-suppressive activities, p53 has a growing list of functionalities that goes beyond triggering apoptosis, senescence, and cell cycle arrest. 123 The problem arises when destabilized p53 mutations hijack its tumor suppressor activities, and p53 malignancy occurs. TP53 is the "Top 1" gene harboring mutations in human cancer.…”

Section: Effects Of P53 Mutations and P53 Isoforms In Cancermentioning

confidence: 99%

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Targeting Biomolecular Condensation and Protein Aggregation against Cancer

et al. 2023

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Biomolecular condensates, membrane-less entities arising from liquid–liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated in degenerative diseases and cancer. This review thoroughly examines the dual nature of biomolecular condensates, spotlighting their role in cancer, particularly concerning the p53 tumor suppressor. Given that over half of the malignant tumors possess mutations in the TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, p53 not only misfolds but also forms biomolecular condensates and aggregates analogous to other protein-based amyloids, thus significantly influencing cancer progression through loss-of-function, negative dominance, and gain-of-function pathways. The exact molecular mechanisms underpinning the gain-of-function in mutant p53 remain elusive. However, cofactors like nucleic acids and glycosaminoglycans are known to be critical players in this intersection between diseases. Importantly, we reveal that molecules capable of inhibiting mutant p53 aggregation can curtail tumor proliferation and migration. Hence, targeting phase transitions to solid-like amorphous and amyloid-like states of mutant p53 offers a promising direction for innovative cancer diagnostics and therapeutics.

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Section: Phase Separation and Transition Of The P53 Tumor Suppressor ...mentioning

confidence: 99%

Section: Modulators Of Phase Separation and Transitionmentioning

confidence: 99%

Section: Effects Of P53 Mutations and P53 Isoforms In Cancermentioning

confidence: 99%

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Targeting Biomolecular Condensation and Protein Aggregation against Cancer

et al. 2023

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“…For instance, one study has shown that, in estrogen-positive breast cancer cells, the expression of a truncated p53 mutant increased BCL-2, thus decreasing their apoptosis in breast cancer cells [ 409 ]. Moreover, evidence has suggested that certain gain-of-function or loss-of-function mutations of the TP53 gene, as found in many cancers, turn p53 into an oncogene [ 410 ]. In this context, it should be considered that TP53 mutations are very common in hepatocellular carcinoma, and their interplay in the regulation of apoptosis and autophagy has not been investigated [ 411 ].…”

Section: Interplay Between Apoptosis and Autophagymentioning

confidence: 99%

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

2023

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The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.

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“…P53 also functions as a protein modulator. During ischemia-related oxidative stress, P53 accumulates in the mitochondrial matrix through its interaction with cyclophilin D, leading to the opening of the permeability transition pore and, ultimately, necrosis [ 8 , 9 ]. P53 also binds to glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate shunt and decreases flux [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants

Nagourney¹,

Gipoor²,

Evans³

et al. 2023

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Background: TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in “hotspots” affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to P53 cysteine residues, altering conformation, while COTI-2 showed activity in P53 mutant tumors by a computational platform. We compared APR-246 and COTI-2 activity in human tumor explants from 247 surgical specimens. Methods: Ex vivo analyses of programmed cell death measured drug-induced cell death by delayed-loss-of-membrane integrity and ATP content. The LC50s were compared by Z-Score. Synergy was conducted by the method of Chou and Talalay, and correlations were performed by Pearson moment. Results: APR-246 and COTI-2 activity favored hematologic neoplasms, but solid tumor activity varied by diagnosis. COTI-2 and APR-246 activity did not correlate (R = 0.1028) (NS). COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. For ovarian cancer, COTI-2 showed synergy with cisplatin at 25%. Conclusions: COTI-2 and APR-246 activity differ by diagnosis. A lack of correlation supports distinct modes of action. Cisplatin synergy is consistent with P53’s role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.

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Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53

Cited by 11 publications

References 311 publications

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants

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