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

Padariya, Monikaben; Jooste, Mia-Lyn; Hupp, Ted R.; Fåhræus, Robin; Vojtesek, Borek; Vollrath, Fritz; Kalathiya, Umesh; Karakostis, Konstantinos

doi:10.1093/molbev/msac149

Cited by 14 publications

(17 citation statements)

References 107 publications

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“…This result contradicts previous results suggesting co-immunoprecipation of p53-R9 with MDM2 [1]. It remains possible that these two proteins interact, but that the interaction is weak as suggested recently by Padariya et al [34]. The mitochondrial pore protein cyclophilin D, which regulates necrotic cell death, co-immunoprecipitated with both elephant and human p53 [35].…”

Section: P53-r9 Binds Chaperone Tid1 To Localize At the Mitochondria ...contrasting

confidence: 88%

Elephant TP53-RETROGENE 9 induces transcription-independent apoptosis at the mitochondria

Preston

Rogers²,

Sharp³

et al. 2023

Cell Death Discov.

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Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes (Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein. Elephant TP53-RETROGENE 9 (TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. This C-terminally truncated p53 retrogene protein lacks the nuclear localization signals and oligomerization domain of its full-length counterpart. When expressed in human osteosarcoma cells (U2OS), p53-R9 binds to Tid1, the chaperone protein responsible for mitochondrial translocation of human p53 in response to cellular stress. Tid1 expression is required for p53-R9-induced apoptosis. At the mitochondria, p53-R9 binds to the pro-apoptotic BCL-2 family member Bax, which leads to caspase activation, cytochrome c release, and cell death. Our data show, for the first time, that expression of this truncated elephant p53 retrogene protein induces apoptosis in human cancer cells. Understanding the molecular mechanism by which the additional elephant TP53 retrogenes function may provide evolutionary insight that can be utilized for the development of therapeutics to treat human cancers.

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Section: P53-r9 Binds Chaperone Tid1 To Localize At the Mitochondria ...contrasting

confidence: 88%

Elephant TP53-RETROGENE 9 induces transcription-independent apoptosis at the mitochondria

Preston

Rogers²,

Sharp³

et al. 2023

Cell Death Discov.

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“…A p53-mediated apoptotic response to SIPs was also observed in a previous study with elephant fibroblasts. It was shown that the expansion of TP53 copy number in elephants (20 copies) with several TP53 retrogenes showing expression could be responsible for this phenotype [14, 15, 50]. We analyzed genomes of several bat species to see if TP53 copy number expansion has occurred in Chiroptera (Figure 7a).…”

Section: Resultsmentioning

confidence: 99%

Limited Cell-Autonomous Anticancer Mechanisms in Long-Lived Bats

Athar,

Zheng,

Riquier

et al. 2024

Preprint

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Bats are remarkably long-lived for their size with many species living more than 20-40 years, suggesting that they possess efficient anti-aging and anti-cancer defenses. Here we investigated requirements for malignant transformation in primary bat fibroblasts in four bat species - little brown bat (Myotis lucifugus), big brown bat (Eptesicus fuscus), cave nectar bat (Eonycteris spelaea) and Jamaican fruit bat (Artibeus jamaicensis), spanning the bat evolutionary tree and including the longest-lived genera. We show that bat fibroblasts do not undergo replicative senescence and express active telomerase. Bat cells displayed attenuated stress induced premature senescence with a dampened secretory phenotype. Unexpectedly, we discovered that bat cells could be readily transformed by only two oncogenic perturbations or hits: inactivation of either p53 or pRb and activation of oncogenic RASV12. This was surprising because other long-lived mammalian species require up to five hits for malignant transformation. Additionally, bat fibroblasts exhibited increased p53 and MDM2 transcript levels, and elevated p53-dependent apoptosis. The little brown bat showed a genomic duplication of the p53 gene. We hypothesize that bats evolved enhanced p53 activity through gene duplications and transcriptional upregulation as an additional anti-cancer strategy, similar to elephants. In summary, active telomerase and the small number of oncogenic hits sufficient to malignantly transform bat cells suggest that in vivo bats rely heavily on non-cell autonomous mechanisms of tumor suppression.

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“…To better understand the p38 paralogs’ fate, we inferred a phylogenetic tree with an extended dataset for vertebrates. We included species relevant for our study such as whales and elephants due to a link between large body size and cancer resistance [29–31] and bats or naked mole rat as animals with a special immune system [32,33]. Altogether, we collected 294 protein sequences from 63 species (electronic supplementary material, table S3).…”

Section: Resultsmentioning

confidence: 99%

Evolutionary analysis of p38 stress-activated kinases in unicellular relatives of animals suggests an ancestral function in osmotic stress

et al. 2023

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p38 kinases are key elements of the cellular stress response in animals. They mediate the cell response to a multitude of stress stimuli, from osmotic shock to inflammation and oncogenes. However, it is unknown how such diversity of function in stress evolved in this kinase subfamily. Here, we show that the p38 kinase was already present in a common ancestor of animals and fungi. Later, in animals, it diversified into three JNK kinases and four p38 kinases. Moreover, we identified a fifth p38 paralog in fishes and amphibians. Our analysis shows that each p38 paralog has specific amino acid substitutions around the hinge point, a region between the N-terminal and C-terminal protein domains. We showed that this region can be used to distinguish between individual paralogs and predict their specificity. Finally, we showed that the response to hyperosmotic stress in Capsaspora owczarzaki , a close unicellular relative of animals, follows a phosphorylation–dephosphorylation pattern typical of p38 kinases. At the same time, Capsaspora 's cells upregulate the expression of GPD1 protein resembling an osmotic stress response in yeasts. Overall, our results show that the ancestral p38 stress pathway originated in the root of opisthokonts, most likely as a cell's reaction to salinity change in the environment. In animals, the pathway became more complex and incorporated more stimuli and downstream targets due to the p38 sequence evolution in the docking and substrate binding sites around the hinge region. This study improves our understanding of p38 evolution and opens new perspectives for p38 research.

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

Cited by 14 publications

References 107 publications

Elephant TP53-RETROGENE 9 induces transcription-independent apoptosis at the mitochondria

Elephant TP53-RETROGENE 9 induces transcription-independent apoptosis at the mitochondria

Limited Cell-Autonomous Anticancer Mechanisms in Long-Lived Bats

Evolutionary analysis of p38 stress-activated kinases in unicellular relatives of animals suggests an ancestral function in osmotic stress

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