Autophagy mediates the mitotic senescence transition

Abstract

As a stress response, senescence is a dynamic process involving multiple effector mechanisms whose combination determines the phenotypic quality. Here we identify autophagy as a new effector mechanism of senescence. Autophagy is activated during senescence and its activation is correlated with negative feedback in the PI3K-mammalian target of rapamycin (mTOR) pathway. A subset of autophagy-related genes are up-regulated during senescence: Overexpression of one of those genes, ULK3, induces autophagy and senescence. Furthermore, inhibition of autophagy delays the senescence phenotype, including senescence-associated secretion. Our data suggest that autophagy, and its consequent protein turnover, mediate the acquisition of the senescence phenotype.Supplemental material is available at http://www.genesdev.org.Received December 24, 2008; revised version accepted February 11, 2009. Cellular senescence is a state of stable cell cycle arrest with active metabolism. Similar to apoptosis, senescence can be a failsafe program against a variety of cellular insults. In contrast to apoptosis, however, in which the cytotoxic signals converge to a common mechanism, senescence is typically a delayed stress response involving multiple effector mechanisms. These effector mechanisms include epigenetic regulation (Narita et al. 2006;Adams 2007), the DNA damage response (Bartkova et al. 2006;Di Micco et al. 2006;Mallette et al. 2007), and the senescence-associated secretion phenotype (Kortlever et al. 2006;Acosta et al. 2008;Coppé et al. 2008;Kuilman et al. 2008;Wajapeyee et al. 2008). The relative contribution of these effectors varies depending on the trigger and cell type.Oncogene-induced senescence (OIS) illustrates well the tumor-suppressive role of senescence (Collado and Serrano 2006). The initial phenotype of oncogene induction is a highly proliferative state, which mimics transformation. However, this mitotic burst is gradually replaced by senescence. Although it has been proposed that global and progressive epigenetic alterations play a crucial role in OIS (Narita et al. 2006), the precise mechanism by which cells can achieve such a dramatic change is still unclear.Autophagy is a genetically regulated program responsible for the turnover of cellular proteins and damaged or superfluous organelles. This evolutionarily conserved process is characterized by the formation of doublemembrane cytosolic vesicles, autophagosomes, which sequester cytoplasmic content and deliver it to lysosomes (Ohsumi 2001;Klionsky et al. 2007;Mizushima et al. 2008). Autophagy is often associated with acute metabolic changes and rapid protein replacement. For example, autophagy is required for preimplantation development, where maternal proteins are recycled by autophagy (Tsukamoto et al. 2008). Autophagy is also required for survival in the early neonatal starvation period (Kuma et al. 2004;Komatsu et al. 2005). In addition to these physiological conditions, cytotoxic stimuli can also activate autophagy, but its precise role as a stress response...

Autophagy at the crossroads of catabolism and anabolism

“…Furthermore, ATGs promote the efficient secretion of cytokines during oncogene-induced senescence and during cancer cell invasion 106,137 . Further dissecting the cellular mechanisms through which autophagy mediators facilitate these diverse secretory processes remains an important topic for future study.…”

Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy

“…A recent report showed that autophagy is required for senescence transition in mammalian cells [40].…”

p62/SQSTM1 at the interface of aging, autophagy, and disease

“…In addition, autophagy is required for chronological lifespan extension in yeast (Alvers et al 2009), and for the longevity response to DR and reduced TOR and insulin signaling in C. elegans, even though its induction alone is not sufficient to extend lifespan (Hansen et al 2008). Inhibiting autophagy triggers premature cellular senescence in human fibroblasts (Kang et al 2011), but it is also required for the senescence transition in response to oncogenic signaling (Young et al 2009), suggesting that autophagy could have pleiotropic effects. Indeed, excessive activation of autophagy can be deleterious and cause cell death independently of apoptosis (Pattingre et al 2005).…”