RESUMO
Giant tortoises are among the longest-lived vertebrate animals and, as such, provide an excellent model to study traits like longevity and age-related diseases. However, genomic and molecular evolutionary information on giant tortoises is scarce. Here, we describe a global analysis of the genomes of Lonesome George-the iconic last member of Chelonoidis abingdonii-and the Aldabra giant tortoise (Aldabrachelys gigantea). Comparison of these genomes with those of related species, using both unsupervised and supervised analyses, led us to detect lineage-specific variants affecting DNA repair genes, inflammatory mediators and genes related to cancer development. Our study also hints at specific evolutionary strategies linked to increased lifespan, and expands our understanding of the genomic determinants of ageing. These new genome sequences also provide important resources to help the efforts for restoration of giant tortoise populations.
Assuntos
Envelhecimento/genética , Genoma , Tartarugas/genética , Animais , Reparo do DNA/genética , Evolução Molecular , Células HEK293 , Humanos , Mediadores da Inflamação , Masculino , Neoplasias/genética , Filogenia , Densidade DemográficaRESUMO
Myeloproliferative neoplasms (MPNs) represent a frequently occurring group of heterogeneous hematologic malignancies. In the last decade, the identification of JAK2-activating mutations in a significant proportion of MPN patients gave rise to the first molecularly driven therapy for BCR-ABL-negative patients. Nevertheless, current efforts are still focused on the identification of novel therapeutic targets to achieve permanent remission. In this perspective, we focus on the recent findings in this field and highlight new evidence linking proteostasis deregulation with myeloid transformation. We recently reported that the proteostasis regulator AIRAPL acts as a tumor suppressor in MPNs through the modulation of insulin-like growth factor receptor levels at the endoplasmic reticulum. This finding paves the way for new therapeutic approaches to these neoplasms and indicates the importance of protein homeostasis maintenance for normal hematopoiesis.
Assuntos
Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/metabolismo , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Predisposição Genética para Doença , Humanos , Terapia de Alvo Molecular , Mutação , Transtornos Mieloproliferativos/terapia , Transdução de Sinais/efeitos dos fármacosRESUMO
AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.