For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.

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Aging, Cellular Senescence, and Cancer

Autophagy and Aging

Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of “cellular senescence” in vivo. It is being recognized as a critical feature of mammalian cells to suppress tumorigenesis, acting alongside cell death programs. Here, we review the various features of cellular senescence and discuss their contribution to tumor suppression. Additionally, we highlight the power and limitations of the biomarkers currently used to identify senescent cells in vitro and in vivo.

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The essence of senescence

Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events - senescence, followed by clearance and then regeneration - may not be efficiently completed in aged tissues or in pathological contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.

Cellular senescence: from physiology to pathology.

Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

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Four faces of cellular senescence

The role of MYC in regulating p53 stability as a function of increased ribosome biogenesis is controversial. On the one hand, it was suggested that MYC drives the overexpression of ribosomal proteins (RP)L5 and RPL11, which bind and inhibit HDM2, stabilizing p53. On the other, it has been proposed that increased ribosome biogenesis leads the consumption of RPL5/RPL11 into nascent ribosomes, reducing p53 levels and enhancing tumorigenesis. Here, we show that the components that make up the recently described impaired ribosome biogenesis checkpoint (IRBC) complex, RPL5, RPL11, and 5S rRNA, are reduced following MYC silencing. This leads to a rapid reduction in p53 protein half-life in an HDM2-dependent manner. In contrast, MYC induction leads to increased ribosome biogenesis and p53 protein stabilization. Unexpectedly, there is no change in free RPL5/RPL11 levels, but there is a striking increase in IRBC complex bound to HDM2. Our data support a cell-intrinsic tumor-suppressor response to MYC expression, which is presently being exploited to treat cancer. SIGNIFICANCE: Oncogenic MYC induces the impaired ribosome biogenesis checkpoint, which could be potentially targeted for cancer treatment.

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Oncogenic MYC Induces the Impaired Ribosome Biogenesis Checkpoint and Stabilizes p53 Independent of Increased Ribosome Content.

Impaired ribosome biogenesis checkpoint activation induces p53-dependent MCL-1 degradation and MYC-driven lymphoma death

Publisher Summary Insulin controls a number of key anabolic responses in specific target tissues including liver, adipose, and muscle including the activation and maintenance of high rates of protein synthesis, which is the most energy consuming process. Insulin signaling regulates the first step of translation initiation by controlling the phosphorylation state of eIF2B. Translation initiation is a highly regulated, dynamic stepwise process. It is classically separated into four steps: formation of the 43S preinitiation complex, which contains eukaryotic initiation factor methionine transfer RNA, the 40S ribosomal subunit, eIF3, and eIF1A; recruitment of the 43S preinitiation complex to the 5’ cap of the messenger RNA by eIF4F leading to the formation of the 48S initiation complex; scanning of the 5’ untranslated region of the mRNA by the eIF 4F complex until reaching the AUG start codon; and recruitment of the 60S subunit to assemble a complete 80S ribosome. Insulin induced activation of PKB/Akt causes phosphorylation and inactivation of GSK3 leading to eIF2B dephosphorylation and consequent activation. In mammalian cells, transit of the 80S ribosome along the mRNA, termed translational elongation, requires two elongation factors: eukaryotic elongation factors 1 and 2 (eEF1 and eEF2). Insulin treatment decreases the activity of eEF2K resulting in dephosphorylation of eEF2, which leads to accelerated rates of elongation. Insulin signaling also regulates ribosome biogenesis leading to increased translational capacity in the cell by two apparent mechanisms: increasing the translation of ribosomal proteins and increasing ribosomal RNA (rRNA) production.

Translation Control and Insulin Signaling

This manuscript represents the second of two lectures concerning the p70s6k and translation. It is presented as closely as possible to the actual talk.

George Thomas

Papers

Oncogenic MYC Induces the Impaired Ribosome Biogenesis Checkpoint and Stabilizes p53 Independent of Increased Ribosome Content.

Impaired ribosome biogenesis checkpoint activation induces p53-dependent MCL-1 degradation and MYC-driven lymphoma death

Translation Control and Insulin Signaling

Rapamycin, FRAP and the Control of 5’TOP mRNA Translation