From Churchill to Elephants: The Role of Protective Genes Against Cancer DOI Open Access
Annalisa Gazzellone, Eugenio Sangiorgi

Published: Dec. 28, 2023

Richard Peto’s Paradox, first described in 1975 from an epidemiological perspective, established inverse correlation between the probability of developing cancer multicellular organisms and number cells. Larger animals exhibit fewer tumors compared to smaller ones, though exceptions exist. Mice are more susceptible than humans, while elephants whales demonstrate significantly lower prevalence rates humans. How nature evolution have addressed issue animal kingdom remains largely unexplored. In field medicine, much attention has been devoted predisposing genes, as they offer avenues for intervention, including blocking, downregulating, early diagnosis, targeted treatment. Predisposing genes also tend manifest clinically earlier aggressively, making them easier identify. However, despite significant strides modern role protective lags behind. Identifying with a mild effect poses challenge. Consequently, comprehending function conferred by becomes even elusive, their very existence is subject questioning. While variable expressivity penetrance defects same variant family well-documented many hereditary syndromes, attempts delineate protective/modifier alleles restricted few instances. this review, we endeavor elucidate observed within certain genetic syndromes that appear act cancer-resistant/repressor alleles. The ultimate goal discern why individuals, like Winston Churchill, managed live up 91 years age, engaging minimal physical activity, consuming large quantities alcohol daily, not abstaining smoking.

Language: Английский

The Role of TP53 in Adaptation and Evolution DOI Creative Commons
Konstantinos Voskarides,

Nefeli Giannopoulou

Cells, Journal Year: 2023, Volume and Issue: 12(3), P. 512 - 512

Published: Feb. 3, 2023

The TP53 gene is a major player in cancer formation, and it considered the most important tumor suppressor gene. p53 protein acts as transcription factor, involved DNA repair, senescence, cell-cycle control, autophagy, apoptosis. Beyond cancer, there evidence that associated with fertility, aging, longevity. Additionally, more exists genetic variants are environmental adaptation. Special amino-acid residues or pathogenic mutations seem to be adaptive for animals living hypoxic cold environments having been exposed starvation, respectively. At somatic level, has recently proven multiple genes, including TP53, under positive selection healthy human tissues. It not clear why these driver do transform tissues into cancerous ones. Other studies have shown elephants copies, probably this being reason very low incidence large animals. This may explain famous Peto’s paradox. review discusses detail multilevel role of adaptation, according published evidence. complicated, extends from cells individuals populations.

Language: Английский

Citations

54
The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway DOI Creative Commons
Konstantinos Karakostis,

Laurence Malbert-Colas,

Aikaterini Thermou

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Jan. 23, 2024

Abstract Background The ATM kinase constitutes a master regulatory hub of DNA damage and activates the p53 response pathway by phosphorylating MDM2 protein, which develops an affinity for mRNA secondary structure. Disruption this interaction prevents activation nascent p53. link protein— with upstream sensor role in sensing mechanism, are still highly anticipated. Methods proximity ligation assay (PLA) has been extensively used to reveal sub-cellular localisation protein—mRNA protein–protein interactions. ELISA co-immunoprecipitation confirmed interactions vitro cells. Results This study provides novel mechanism whereby interacts enzyme shows that L22L synonymous mutant, known alter structure mRNA, interaction. relevant mechanistic roles Damage Sensing pathway, is linked downstream response, explored. Following (double-stranded breaks activating ATM), activated MDMX protein competes ATM— association NBS1 (MRN complex). These data also binding domains phosphorylation events on regulate trafficking complex cytoplasm. Conclusion presented model describes between pathways; supporting rising functional implications mutations altering structures.

Language: Английский

Citations

10
Why Do Elephants Rarely Get Cancer? Exploring Genomic Evolutionary Adaptations and the Role of a Tumor Suppressor Gene DOI Creative Commons
Kristen Clapper Bergsman,

Peggy O’Neill Skinner,

L. Matthews

et al.

The Science Teacher, Journal Year: 2025, Volume and Issue: 92(2), P. 76 - 86

Published: March 3, 2025

Language: Английский

Citations

0
Natural resistance to cancers in long-lived mammals: genomic mechanisms and experimental evidence to explain Peto’s paradox DOI

Linxia Sun,

Zhi‐Kang Xu,

Mengqi Shuai

et al.

Science China Life Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Language: Английский

Citations

0
Elephant TP53-RETROGENE 9 induces transcription-independent apoptosis at the mitochondria DOI Creative Commons
Aidan J. Preston,

Aaron Rogers,

Miranda Sharp

et al.

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: Feb. 16, 2023

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

Language: Английский

Citations

7
Do elephants really never forget? What we know about elephant memory and a call for further investigation DOI

Sydney F. Hope,

Kaitlyn Rose Willgohs,

Sangpa Dittakul

et al.

Learning & Behavior, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 22, 2024

Language: Английский

Citations

2
Limited Cell-Autonomous Anticancer Mechanisms in Long-Lived Bats DOI Creative Commons
Fathima Athar, Zhizhong Zheng, Sébastien Riquier

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 29, 2024

ABSTRACT 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 malignant transformation in primary bat fibroblasts four - little brown ( Myotis lucifugus) , big Eptesicus fuscus ), cave nectar Eonycteris spelaea ) Jamaican fruit Artibeus jamaicensis – spanning the evolutionary tree including longest-lived genera. We show do not undergo replicative senescence express active telomerase. Bat cells displayed attenuated stress induced premature a dampened secretory phenotype. Unexpectedly, discovered could be readily transformed by only two oncogenic perturbations or “hits”: inactivation of either p53 pRb activation RASV12. This was surprising because other mammalian require up to five hits transformation. Additionally, exhibited increased MDM2 transcript levels, elevated p53-dependent apoptosis. The showed genomic duplication gene. hypothesize bats evolved enhanced activity through gene duplications transcriptional upregulation as an additional strategy, similar elephants. In summary, telomerase small number sufficient malignantly transform suggest vivo rely heavily on non-cell autonomous mechanisms tumor suppression.

Language: Английский

Citations

2
Chromosome‐level Asian elephant genome assembly and comparative genomics of long‐lived mammals reveal the common substitutions for cancer resistance DOI Creative Commons
Xuanjing Li, Pengcheng Wang, Qi Pan

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 22(9)

Published: July 3, 2023

Abstract The naked mole rat ( Heterocephalus glaber ), bats (e.g., genus Myotis and elephants (family Elephantidae) are known as long‐lived mammals assumed to be excellent cancer antagonists. However, whether there common genetic changes underpinning resistance in these species is yet fully established. Here, we newly generated a high‐quality chromosome‐level Asian elephant Elephas maximus ) genome identified that the expanded gene families involved Ras‐associated base excision repair pathways. Moreover, performed comparative genomic analyses of 12 examined genes with signatures positive selection elephants, rat, greater horseshoe bat. Residues at positively selected sites CDR2L ALDH6A1 enhanced inhibition tumor cell migration compared those short‐lived relatives. Overall, our study provides new resource preliminary survey mammals.

Language: Английский

Citations

5
Evolutionary analysis of p38 stress-activated kinases in unicellular relatives of animals suggests an ancestral function in osmotic stress DOI Creative Commons
Victoria Shabardina, Pedro Romero Charria, Gonzalo Bercedo Saborido

et al.

Open Biology, Journal Year: 2023, Volume and Issue: 13(1)

Published: Jan. 1, 2023

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

Language: Английский

Citations

4
From Churchill to Elephants: The Role of Protective Genes against Cancer DOI Open Access
Annalisa Gazzellone, Eugenio Sangiorgi

Genes, Journal Year: 2024, Volume and Issue: 15(1), P. 118 - 118

Published: Jan. 18, 2024

Richard Peto’s paradox, first described in 1975 from an epidemiological perspective, established inverse correlation between the probability of developing cancer multicellular organisms and number cells. Larger animals exhibit fewer tumors compared to smaller ones, though exceptions exist. Mice are more susceptible than humans, while elephants whales demonstrate significantly lower prevalence rates humans. How nature evolution have addressed issue animal kingdom remains largely unexplored. In field medicine, much attention has been devoted cancer-predisposing genes, as they offer avenues for intervention, including blocking, downregulating, early diagnosis, targeted treatment. Predisposing genes also tend manifest clinically earlier aggressively, making them easier identify. However, despite significant strides modern role protective lags behind. Identifying with a mild predisposing effect poses challenge. Consequently, comprehending function conferred by becomes even elusive, their very existence is subject questioning. While variable expressivity penetrance defects same variant family well-documented many hereditary syndromes, attempts delineate protective/modifier alleles restricted few instances. this review, we endeavor elucidate observed kingdom, within certain genetic syndromes that appear act cancer-resistant/repressor alleles. Additionally, explore conditions cancer. The ultimate goal discern why individuals, like Winston Churchill, managed live up 91 years age, engaging minimal physical activity, consuming large quantities alcohol daily, not abstaining smoking.

Language: Английский

Citations

1