Adaptive homeostasis and the p53 isoform network

Mehta, Sunali; Campbell, Heather; Drummond, Catherine J.; Li, Kunyu; Murray, Kaisha; Slatter, Tania L.; Bourdon, Jean-Christophe; Braithwaite, Antony W.

doi:10.15252/embr.202153085

Cited by 27 publications

(22 citation statements)

References 282 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Insights into structural modifications and activation toward signaling mechanisms, illuminate the factors that prevent or promote carcinogenesis. Studies on the p53 isoforms ( Zhang et al 2019 ; Levandowski et al 2021 ) will help to illuminate how their respective activities are regulated in response to cellular damages and pathogen infections ( Breton et al 2021 ; Mehta et al 2021 ). This will not only result in a better understanding of p53 roles and regulation in elephants and in its role in protecting elephants from cancers as well as probably other “inflictions”, such as parasites ( Lynsdale et al 2017 ), but it also facilitates the development of new therapeutic strategies for human, based on structural molecular data.…”

Section: Discussionmentioning

confidence: 99%

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

Padariya

Jooste

Hupp

et al. 2022

Molecular Biology and Evolution

View full text Add to dashboard Cite

The p53 tumour suppressor is a transcription factor with roles in cell development, apoptosis, oncogenesis, ageing and homeostasis in response to stresses and infections. p53 is tightly regulated by the MDM2 E3 ubiquitin ligase. The p53-MDM2 pathway has co-evolved, with MDM2 remaining largely conserved while the TP53 gene morphed into various isoforms. Studies on pre-vertebrate ancestral homologues revealed the transition from an environmentally-induced mechanism activating p53 to a tightly regulated system involving cell signaling. The evolution of this mechanism depends on structural changes in the interacting protein motifs. Elephants such as Loxodonta africana constitute ideal models to investigate this co-evolution as they are large and long-living as well as having 20 copies of TP53 isoformic sequences expressing a variety of BOX-I MDM2-binding motifs. Collectively, these isoforms would enhance sensitivity to cellular stresses, such as DNA damage, presumably accounting for strong cancer defenses and other adaptations favouring healthy ageing. Here we investigate the molecular evolution of the p53-MDM2 system by combining in silico modelling and in vitro assays to explore structural and functional aspects of p53 isoforms retaining the MDM2 interaction while forming distinct pools of cell-signalling. The methodology used demonstrates, for the first time, that in silico docking simulations can be used to explore functional aspects of elephant p53 isoforms. Our observations elucidate structural and mechanistic aspects of p53 regulation, facilitate understanding of complex cell signalling and suggest testable hypotheses of p53 evolution referencing Peto’s Paradox.

show abstract

Section: Discussionmentioning

confidence: 99%

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

Padariya

Jooste

Hupp

et al. 2022

Molecular Biology and Evolution

View full text Add to dashboard Cite

show abstract

“…Of note, preclinical models clearly indicate that p53 protects from damage-induced lung impairment antagonizing NF-kB mediated inflammatory/immune responses ( Uddin and Barabutis, 2020 ). Moreover, the experience coming from tumor biology suggests that NF-κB activation counterbalance the pro-apoptotic activity of p53 by affecting p53 viability through MDM2 induction ( Luo et al, 2005 ), in line with the similarities between tumorigenesis process and those related to viral infection and host-virus interaction ( Mehta et al, 2021 ).…”

Section: Introductionmentioning

confidence: 91%

p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics)

et al. 2022

View full text Add to dashboard Cite

SARS-CoV-2 infection affects different organs and tissues, including the upper and lower airways, the lung, the gut, the olfactory system and the eye, which may represent one of the gates to the central nervous system. Key transcriptional factors, such as p53 and NF-kB and their reciprocal balance, are altered upon SARS-CoV-2 infection, as well as other key molecules such as the virus host cell entry mediator ACE2, member of the RAS-pathway. These changes are thought to play a central role in the impaired immune response, as well as in the massive cytokine release, the so-called cytokine storm that represents a hallmark of the most severe form of SARS-CoV-2 infection. Host genetics susceptibility is an additional key side to consider in a complex disease as COVID-19 characterized by such a wide range of clinical phenotypes. In this review, we underline some molecular mechanisms by which SARS-CoV-2 modulates p53 and NF-kB expression and activity in order to maximize viral replication into the host cells. We also face the RAS-pathway unbalance triggered by virus-ACE2 interaction to discuss potential pharmacological and pharmacogenomics approaches aimed at restoring p53/NF-kB and ACE1/ACE2 balance to counteract the most severe forms of SARS-CoV-2 infection.

show abstract

“…These studies demonstrated that p53 isoforms can mediate their network without relying on p53. Furthermore, several signaling pathways interact with the p53 pathway in a p53-isoforms-dependent manner (Figure 4) [75,80]. to affect biological activities such as cell cycle arrest, senescence, apoptosis, and DNA DAB repair by inducing (green line) or repressing (red line) p53 target gene expression.…”

Section: Influence Of the P53 Isoform Network On Biological Processesmentioning

confidence: 99%

p53 Isoforms as Cancer Biomarkers and Therapeutic Targets

Zhao

Sanyal

2022

Cancers

View full text Add to dashboard Cite

This review aims to summarize the implications of the major isoforms of the tumor suppressor protein p53 in aggressive cancer development. The current knowledge of p53 isoforms, their involvement in cell-signaling pathways, and their interactions with other cellular proteins or factors suggests the existence of an intricate molecular network that regulates their oncogenic function. Moreover, existing literature about the involvement of the p53 isoforms in various cancers leads to the proposition of therapeutic solutions by altering the cellular levels of the p53 isoforms. This review thus summarizes how the major p53 isoforms Δ40p53α/β/γ, Δ133p53α/β/γ, and Δ160p53α/β/γ might have clinical relevance in the diagnosis and effective treatments of cancer.

show abstract

Adaptive homeostasis and the p53 isoform network

Cited by 27 publications

References 282 publications

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics)

p53 Isoforms as Cancer Biomarkers and Therapeutic Targets

Contact Info

Product

Resources

About