RESUMO
MYC is one of the most dysregulated oncogenes and is thought to be fundamental to tumor formation and/or maintenance in many cancer types. This dominant pro-tumor activity makes MYC an attractive target for cancer therapy. However, MYC is a transcription factor lacking enzymatic activity, and the structure of one of its two domains is unknown e.g., its transactivation domain. Consequently, few direct MYC-targeting therapies have been developed, and none have been successful in the clinic. Nevertheless, significant effort has been devoted to understanding the mechanisms of oncogenic MYC activity with the objective of uncovering novel vulnerabilities of MYC-dependent cancers. These extensive investigations have revealed in detail how MYC translocation, amplification, and other upstream perturbations contribute to MYC activity in cancer. However, missense mutations of the MYC gene have remained relatively understudied for their potential role in MYC-mediated oncogenesis. While the function of several low-frequency mutations in MYC have been described, our understanding of other equally or more frequent mutations is incomplete. Herein, we define the function of a recurrent missense mutation in MYC resulting in the substitution S146L. This mutation enhances the interaction between MYC and its cofactor TRRAP and may enhance oncogenic MYC activity in certain cellular contexts.
Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-myc , HumanosRESUMO
Skeletal progenitor/stem cells (SSCs) play a critical role in postnatal bone growth and maintenance. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in self-renewing tissues. Here we investigated the role of mTert-expressing cells in postnatal mouse long bone and found that mTert expression is enriched at the time of adolescent bone growth. mTert-GFP+ cells were identified in regions known to house SSCs, including the metaphyseal stroma, growth plate, and the bone marrow. We also show that mTert-expressing cells are a distinct SSC population with enriched colony-forming capacity and contribute to multiple mesenchymal lineages, in vitro. In contrast, in vivo lineage-tracing studies identified mTert+ cells as osteochondral progenitors and contribute to the bone-forming cell pool during endochondral bone growth with a subset persisting into adulthood. Taken together, our results show that mTert expression is temporally regulated and marks SSCs during a discrete phase of transitional growth between rapid bone growth and maintenance.
Assuntos
Células Epiteliais/metabolismo , Células-Tronco/metabolismo , Telomerase/metabolismo , Animais , Medula Óssea/metabolismo , Ciclo Celular/fisiologia , Proliferação de Células/fisiologia , Senescência Celular/fisiologia , CamundongosRESUMO
The cellular and molecular mechanisms underlying adaptive changes to physiological stress within the intestinal epithelium remain poorly understood. Here, we show that PTEN, a negative regulator of the PI3KâAKTâmTORC1-signaling pathway, is an important regulator of dormant intestinal stem cells (d-ISCs). Acute nutrient deprivation leads to transient PTEN phosphorylation within d-ISCs and a corresponding increase in their number. This release of PTEN inhibition renders d-ISCs functionally poised to contribute to the regenerative response during re-feeding via cell-autonomous activation of the PI3KâAKTâmTORC1 pathway. Consistent with its role in mediating cell survival, PTEN is required for d-ISC maintenance at baseline, and intestines lacking PTEN have diminished regenerative capacity after irradiation. Our results highlight a PTEN-dependent mechanism for d-ISC maintenance and further demonstrate the role of d-ISCs in the intestinal response to stress.