Consequently, autophagy can be detected biochemically (by assessing the generation of LC3-II) or microscopically (by observing the formation of LC3 puncta, representative of LC3 redistribution to the developing autophagosomes). In the Atg8 system, Atg8/LC3 undergoes proteolytic processing and covalent attachment to the lipid phosphatidylethanolamine (in mammalian cells, the precursor form is termed LC3-I and the lipidated form LC3-II), by which it becomes associated with the phagophore membrane. Both systems require the E1-like protein autophagy-related gene 7 (Atg7) for activation of the ubiquitin-like proteins Atg8 and Atg12. Downstream of these complexes are two ubiquitin-like conjugation systems that mediate vesicle expansion. The PtdIns3K complex produces phosphatidylinositol 3-phosphate (PtdIns3P) for recruitment of additional autophagy factors to the phagophore and is partially comprised of the key autophagy regulators vacuolar protein sorting 34 (Vps34), Beclin 1, vacuolar protein sorting 15 (Vps15), and activating molecule in Beclin 1-regulated autophagy (AMBRA1). In short, the initiation phase of autophagy is governed by two main complexes: the unc-51-like autophagy-activating kinase (ULK) complex and the class III phosphatidylinositol 3-kinase (PtdIns3K) complex (Figure 1A). The molecular pathway that orchestrates the initiation and execution of autophagy has been comprehensively reviewed elsewhere ( 3– 5). Moreover, the autophagic flux can be upregulated in response to a wide range of stresses, such as nutrient deprivation, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens, whereby it functions as an adaptive cytoprotective response ( 1, 2). In physiological conditions, autophagy proceeds at a basal level to ensure the turnover of superfluous or damaged components, including organelles and long-lived proteins, to maintain cellular homeostasis. The autophagosome finally undergoes fusion with lysosomes whereby the enclosed cargo is degraded and subsequently released and recycled to support cellular metabolism. This is achieved by the formation and expansion of an isolation membrane (or phagophore) that fuses to engulf cytoplasmic constituents in a double-membrane autophagic vacuole (the autophagosome). Macroautophagy (herein referred to as autophagy) is a highly conserved catabolic pathway that mediates the sequestration and delivery of cytoplasmic material to the lysosome for degradation. Furthermore, key findings involving nonautophagic functions for autophagy-related factors in cell-cycle regulation will be addressed. In this review, we will discuss our current knowledge of the reciprocal regulation connecting the autophagy pathway and cell-cycle progression. These advances have obvious implications for our understanding of the intricate relationship between autophagy and cancer. ![]() In recent years, a considerable correlation has emerged between autophagy induction and stress-related cell-cycle responses, as well as unexpected roles for autophagy factors and selective autophagic degradation in the process of cell division. Defective autophagy has been linked to a number of human pathologies, including neoplastic transformation, even though autophagy can also sustain the growth of tumor cells in certain contexts. However, in response to various stresses, the pathway can be further induced to mediate cytoprotection. Under basal conditions, autophagy plays a homeostatic function. 3Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children’s Hospital, Rome, ItalyĪutophagy is a self-degradation pathway, in which cytoplasmic material is sequestered in double-membrane vesicles and delivered to the lysosome for degradation.2Department of Biology, University of Rome Tor Vergata, Rome, Italy.1Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.Daniela De Zio 1* and Francesco Cecconi 1,2,3*
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