Structural Aspects of the p53 Protein in Relation to Gene Evolution: A Second Look

doi:10.1006/jmbi.1996.0425

Journal of Molecular Biology

Volume 260, Issue 5, 2 August 1996, Pages 623-637

https://doi.org/10.1006/jmbi.1996.0425 Get rights and content

Abstract

Several years ago, a comparison of the amino acid sequences of p53 proteins from a variety of species enabled us to reveal structural features of this protein, giving clues to its function. Since then, numerous studies on the biochemical, immunological and biological functions of p53 as well as on its structure (including crystallography data) have provided considerable insight into the multifunctional aspects of p53. The purpose of this review is to present the most recent data concerning the various structural features of the p53 protein with special emphasis on its flexibility, which plays a key role in regulation of its biological activity.

References (0)

Cited by (196)

p53 at the crossroad between mitochondrial reactive oxygen species and necroptosis
2023, Free Radical Biology and Medicine
p53 is a redox-sensitive transcription factor that can regulate multiple cell death programs through different signaling pathways. In this review, we assess the role of p53 in the regulation of necroptosis, a programmed form of lytic cell death highly involved in the pathophysiology of multiple diseases. In particular, we focus on the role of mitochondrial reactive oxygen species (mtROS) as essential contributors to modulate necroptosis execution through p53. The enhanced generation of mtROS during necroptosis is critical for the correct interaction between receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and 3 (RIPK3), two key components of the functional necrosome. p53 controls the occurrence of necroptosis by modulating the levels of mitochondrial H₂O₂ via peroxiredoxin 3 and sulfiredoxin. Furthermore, in response to increased levels of H₂O₂, p53 upregulates the long non-coding RNA necrosis-related factor, favoring the translation of RIPK1 and RIPK3. In parallel, a fraction of cytosolic p53 migrates into mitochondria, a process notably involved in necroptosis execution via its interaction with the mitochondrial permeability transition pore. In conclusion, p53 is located at the intersection between mtROS and the necroptosis machinery, making it a key protein to orchestrate redox signaling during necroptosis.
Butein inhibits cancer cell growth by rescuing the wild-type thermal stability of mutant p53
2023, Biomedicine and Pharmacotherapy
p53 is a transcription factor that activates the expression of various genes involved in the maintenance of genomic stability, and more than 50% of cancers harbor inactivating p53 mutations, which are indicative of highly aggressive cancer and poor prognosis. Pharmacological targeting of mutant p53 to restore the wild-type p53 tumor-suppressing function is a promising strategy for cancer therapy. In this study, we identified a small molecule, Butein, that reactivates mutant p53 activity in tumor cells harboring the R175H or R273H mutation. Butein restored wild-type-like conformation and DNA-binding ability in HT29 and SK-BR-3 cells harboring mutant p53-R175H and mutant p53-R273H, respectively. Moreover, Butein enabled the transactivation of p53 target genes and decreased the interactions of Hsp90 with mutant p53-R175H and mutant p53-R273H proteins, while Hsp90 overexpression reversed targeted p53 gene activation. In addition, Butein induced thermal stabilization of wild-type p53, mutant p53-R273H and mutant p53-R175H, as determined via CETSA. From docking study, we further proved that Butein binding to p53 stabilized the DNA-binding loop-sheet-helix motif of mutant p53-R175H and regulated its DNA-binding activity via an allosteric mechanism, conferring wild-type-like the DNA-binding activity of mutant p53. Collectively, the data suggest that Butein is a potential antitumor agent that restores p53 function in cancers harboring mutant p53-R273H or mutant p53-R175H.
Butein restores the ability of mutant p53 to bind DNA by reversing its transition to the Loop3 (L3) state, endows p53 mutants with thermal stability and re-establishes their transcriptional activity to induce cancer cell death.
Molecular characterization, expression, and H<inf>2</inf>O<inf>2</inf> induction of p53 and mdm2 in the ricefield eel, Monopterus albus
2021, Aquaculture Reports
Citation Excerpt :
In this study, we obtained the ORF sequences of p53 and mdm2 from the gonads of M. albus and analysed their sequence features. The results showed that M. albus p53 was highly conserved between bony fish and mammals, including species such as Homo sapiens, Mesocricetus auratus and Oryzias latipes (Albor et al., 2010; Chen et al., 2001; Krause et al., 1997; Karim and Ali, 2009; Soussi and May, 1996). The Mdm2 of M. albus was highly conserved in relation to the sequences of other vertebrates, including M. musculus and H. sapiens (Fahraeus and Olivaresillana, 2014; Okoro et al., 2012).
The proteins P53 and Mdm2 (murine double minute 2) play a prominent role in preventing the induction of uncontrolled apoptosis in numerous cell types. To better understand their potential roles during gonadal development in Monopterus albus, p53 and mdm2 homologues were isolated and characterized, and their mRNA expression patterns in developing gonadal and ovarian tissue incubated with H₂O₂ in vitro were analysed. The open reading frames (ORFs) of p53 and mdm2 consisted of 1125 and 1497 base pairs (bp), respectively. A multiple amino acid residue alignment analysis showed that p53 and Mdm2 harboured the typical conserved domains of their gene families. Phylogenetic analysis also demonstrated that the Mdm2 of M. albus exhibited high sequence similarity with Lates calcarifer; however, the p53 sequences of the Neoteleostei, including M. albus, were distinct from those of the Euteleostei and other vertebrates. Quantitative real-time PCR revealed that p53 and mdm2 were mainly expressed in the ovary; their expression was significantly increased in the previtellogenic stage, was maintained at the increased level thereafter, showed a second increase in the early intersexual stage, and then decreased with the natural sex change from female to male. After incubation with H₂O₂, the expression patterns of p53 and mdm2 in ovarian fragments were similar to that of the apoptotic molecular marker caspase3, showing a significant increase at 1 h post incubation (hpi), a decrease after 2 hpi, and then a return to significantly upregulated levels at 4 hpi and 8 hpi. In addition, p53, mdm2 and caspase3 were strongly correlated. These results will be useful for further studies on the function and regulation of p53 and Mdm2 during gonadal development in Monopterus albus, particularly in the ovary.
Identification and characterisation of Emp53, the homologue of human tumor suppressor p53, from Echinococcus multilocularis: Its role in apoptosis and the oxidative stress response
2015, International Journal for Parasitology
Citation Excerpt :
The deduced protein sequence (692 amino acids) was then aligned with well-characterised members of the p53 family and human p63 and p73. As shown in Fig. 1A, significant similarity between Emp53 and the vertebrate p53 family is mostly limited to the regions involved in DNA binding (conserved regions II–V) (Soussi and May, 1996). Six out of eight amino acids implicated in DNA binding (Cho et al., 1994) are conserved in Emp53, and one is similar.
Larvae of the fox tapeworm, Echinococcus multilocularis, cause alveolar echinococcosis, which is considered to be the most lethal helminthic infection in humans. Since it develops in host organs, the parasite must have evolved a stress defense system to cope with various genotoxic and cellular stresses that may cause DNA damage and genomic instability. Tumor suppressor p53, well known as the “guardian of the genome”, plays a vital role in response to many types of stress and damage. In the present study, we describe the characterisation of Emp53 from E. multilocularis and demonstrate that it is a structural and functional homologue of mammalian tumor suppressor p53. We show that Emp53 binds specifically to oligonucleotides containing conventional p53 binding sites, indicating that it exhibits a function as a DNA binding transcription factor. Inhibition of Emp53 function can suppress UV irradiation-induced apoptosis in the E. multilocularis metacestode, indicating an important role of Emp53 in the induction of apoptosis following DNA damage. We also reveal that Emp53 plays important roles in resistance to oxidative stress and regulation of oxidative stress-induced apoptosis. Our results suggest that, similar to its human counterpart, Emp53 plays a central role in the network of DNA damage responses and apoptosis in E. multilocularis. These results may help in exploring stress defense mechanisms of parasitic helminths and may provide useful information for the development of new interventions and therapeutic drugs for the control of alveolar echinococcosis.
Cyclopenta[c]phenanthrenes - Chemistry and biological activity
2013, Chemico-Biological Interactions
Despite cyclopenta-fused polycyclic aromatic hydrocarbons (CP-PAHs) having been detected in the environment, the ability of these compounds to induce cellular and tissue responses remains poorly characterized. In this review, we look at the chemistry and biological activity of the cyclopenta[c]phenanthrenes (CP[c]Phs) as potential chemicals of concern in the process of risk assessment. The first part of the review deals with the environmental occurrence and chemistry of CP-PAHs, focusing on available methods of CP[c]Ph chemical synthesis. The most interesting structural feature of the CP[c]Ph is the presence of a pseudo fjord-region constructed by the cyclopentane ring. This compound can be treated either as a structurally similar one to B[c]Ph, or as a phenanthrene skeleton with an electrodonating alkyl substituent in the bay-region of the molecule. The second thread, providing available data on the adverse effects of CP[c]Ph compounds on cells and tissues of living organisms, mainly fish, improves our understanding of these possible environmental hazards. The data show that CP[c]Ph is less potent at inducing CYP1A gene expression in rainbow trout than benzo[a]pyrene (B[a]P), a well-known Ah-receptor agonist. Interestingly, the CP[c]Ph dependent up-regulation of CYP1A mRNA is positively correlated with the incidences of clastogenic changes in rainbow trout erythrocytes. CP[c]Ph has, comparably to B[a]P, a potential to repress expression of tumor suppressor p53, in the head kidney of rainbow trout. Furthermore, estrogen responsive genes in fish liver, ERα and VTG, are not induced by CP[c]Ph, suggesting that the compound has no endocrine disrupting potential. However, some CP[c]Phs show mutagenic activity when investigated in the Ames test, and exhibit genotoxic properties in in vitro micronucleus assay. The above characteristics suggest that CP-PAHs are chemicals of concern for which potential pathways of exposure should be further identified.
Role of TP53 Arg72Pro polymorphism in urinary bladder cancer predisposition and predictive impact of proline related genotype in advanced tumors in an ethnic Kashmiri population
2010, Cancer Genetics and Cytogenetics
Citation Excerpt :
TP53, a representative tumor suppressor, gene located on chromosome 17p13, is one of the most commonly mutated genes in all types of human cancer [5,6]. It is responsible for the transcription of a site-specific DNA-binding protein and acts as a transcription factor of cell growth–regulator genes [7]. It has been revealed that TP53 somatic mutations are found primarily in high-grade and invasive bladder tumors, contributing about 35–72% of muscle-invasive bladder tumors [8,9].
Among various polymorphic variants of TP53 gene, codon 72 polymorphism (Arg72Pro) has been found to be associated with cancer susceptibility, but only few studies have investigated their effect on bladder cancer risk. A case–control study was conducted and we observed the genotype distribution of TP53 Arg72Pro SNP, to elucidate the possible role of this SNP as risk factor in urinary bladder cancer (UBC) development and to examine its correlation with the clinicopathologic variables of UBC cases. Using the polymerase chain reaction-restriction fragment length polymorphism approach, we tested the genotype distribution of 108 bladder cancer patients in comparison with 138 cancer-free controls from the same geographical region. We observed significant differences between the control and bladder cancer patients with odds ratio = 2.9 and 95% confidence interval = 1.5–4.5 (P = 0.00001). Interestingly, the proline form was abundantly observed in advanced tumors (P < 0.05). We also found a significant association of the variant allele (GC+CC) with male subjects and ever smokers (P = 0.001). Thus, it is evident from our study that Arg72Pro SNP is implicated in bladder cancer, and that the rare, proline-related allele is connected with higher susceptibility to bladder cancer.

View all citing articles on Scopus

^f1: Corresponding author

View full text

Journal of Molecular Biology

Review ArticleStructural Aspects of the p53 Protein in Relation to Gene Evolution: A Second Look

Abstract

Review Article
Structural Aspects of the p53 Protein in Relation to Gene Evolution: A Second Look