Myc-Dependent Genome Instability and Lifespan in Drosophila

Greer, Christina; Lee, Moonsook; Westerhof, R G Maaike; Milholland, Brandon; Spokony, Rebecca; Vijg, Jan; Secombe, Julie

doi:10.1371/journal.pone.0074641

Cited by 43 publications

(42 citation statements)

References 57 publications

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“…Myc haploinsufficiency in Drosophila also extends lifespan, pointing to a deep conservation of the underlying processes (Greer et al, 2013). Myc +/− mice display ameliorated aging phenotypes across a variety of pathophysiological processes in multiple organs, the breadth of which suggests that their increased longevity is not attributable to the prevention of a specific fatal disease, but rather to a broadly increased healthspan.…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

Hofmann

Zhao

Cecco

et al. 2015

Cell

264

294

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SUMMARY MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/−) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR and S6K activities. In contrast to observations in other longevity models, Myc+/− mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

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Section: Discussionmentioning

confidence: 99%

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

Hofmann

Zhao

Cecco

et al. 2015

Cell

264

294

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“…Intriguingly, reduced levels of Myc also increase the lifespan of flies (Greer et al, 2013) and mice (Hofmann et al, 2015) and are associated with lowered nucleo-cytosolic acetyl-CoA levels (Edmunds et al, 2014;Morrish et al, 2010). Along similar lines, nucleo-cytosolic acetylCoA metabolism has been genetically linked to autophagy regulation and lifespan in yeast and Drosophila melanogaster .…”

Section: Catabolism and Autophagymentioning

confidence: 93%

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

et al. 2015

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Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger.

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“…In mammalian cells and Drosophila, overexpression of Myc increases the frequency of chromosomal rearrangements (Prochownik and Li 2007;Greer et al 2013). Multiple mechanisms have been associated with such genomic rearrangements, including ROS-induced DSBs, suppression of checkpoints that prevent replication of damaged DNA, and telomere clustering.…”

Section: Genomic Instabilitymentioning

confidence: 99%

Signal Transduction in Cancer

Grainger

Brugge

2015

Cold Spring Harbor Perspectives in Medicine

777

455

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SUMMARYCancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.

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Myc-Dependent Genome Instability and Lifespan in Drosophila

Cited by 43 publications

References 57 publications

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Signal Transduction in Cancer

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