1. Autophagy 엄 상 경 Autophagy in the Pathogenesis of Disease
Control of autophagy by oncogenes and tumor suppressor genes
엄 상 경

2. Autophagy
＊ Autophagy
Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development and homeostasis.
Autophagy principally serves an adaptive role to protect organisms against diverse pathologies, including infections, cancer, neurodegeneration, aging, and heart disease.
However, in certain experimental disease settings, the self-cannibalistic or, paradoxically, even the prosurvival functions of autophagy may be deleterious.
This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
Cell Jan 11;132(1):27-42

3. Autophagy ＊ Different types of Autophagy
Macroautophagy, the cargoes are sequestered within a unique double membrane cytosolic vesicle, an autophagosome. Sequestration can be either nonspecific, involving the engulfment of bulk cytoplasm, or selective, targeting specific cargoes such as organelles or invasive microbes.
Microautophagy refers to the sequestration of cytosolic components directly by lysosomes through invaginations in their limiting membrane.
Chaperone-mediated autophagy(CMA) involves direct translocation of unfolded substrate proteins across the lysosome membrane through the action of a cytosolic and lysosomal chaperone hsc70, and the integral membrane receptor LAMP-2A (lysosome-associated membrane protein type 2A).
Nature Feb 28;451(7182):

4. Autophagy ＊ Different types of Autophagy
Macroautophagy : the major regulated catabolic mechanism that eukaryotic cells use to degrade long-lived proteins and organelles.
Nature Feb 28;451(7182):

5. Autophagy
＊ The Cellular, Molecular, and Physiological Aspects of Autophagy
Cell Jan 11;132(1):27-42

6. Autophagy ＊ Molecular pathways
There are more than 20 genes in yeast (known as the ATG genes) that encode proteins (many of which are evolutionarily conserved) that are essential for the
execution of autophagy. These include a protein serine/threonine kinase complex that responds to upstream signals such as TOR kinase (Atg1, Atg13,
Atg17), a lipid kinase signaling complex that mediates vesicle nucleation (Atg6, Atg14, Vps34, and Vps15), two ubiquitin-like conjugation pathways that mediate vesicle expansion (the Atg8 and Atg12 systems), a recycling pathway that mediates the disassembly of Atg proteins from mature autophagosomes (Atg2,
Atg9, Atg18), and vacuolar permeases that permit the efflux of amino acids from the degradative compartment (Atg22). In mammals, proteins that act more generally in lysosomal function are required for proper fusion with autophagosomes—such as the lysosomal transmembrane proteins, LAMP-2 and CLN3—and for the degradation of autophagosomal contents, such as the lysosomal cysteine proteases, cathepsins B, D, and L.
Cell Jan 11;132(1):27-42

7. Autophagy ＊ Molecular pathways
J. Clin. Invest. 115:2679–2688 (2005).; Cell Jan 11;132(1):27-42

8. Autophagy ＊ The phagophore assembly site
Nat Cell Biol Oct;9(10):

9. Autophagy ＊ Physiological Functions of Autophagy
# Autophagy Defends against Metabolic Stress
A critical physiological role of autophagy appears to be the mobilization of intracellular energy resources to meet cellular and organismal demands for metabolic substrates.
This hypothesis may explain why there are high levels of autophagy in the mouse heart and diaphragm immediately following birth.
Cell Jan 11;132(1):27-42.; Cell Jan 28;120(2):

10. Autophagy ＊ Physiological Functions of Autophagy
# Autophagy Works as a Cellular Housekeeper
The repertoire of routine housekeeping functions performed by autophagy includes the elimination of defective proteins and organelles, the prevention of abnormal protein aggregate accumulation, and the removal of intracellular pathogens.
some of these functions overlap with those of the ubiquitin-proteosome system, the autophagy pathway is uniquely capable of degrading entire organelles such as mitochondria, peroxisomes, and ER as well as intact intracellular microorganisms.
The relative role of the autophagy-lysosome system in protein quality control.
Cell Jan 11;132(1):27-42.

11. Autophagy ＊ Physiological Functions of Autophagy
# Autophagy Works as a Cellular Housekeeper
Cell Jan 11;132(1):27-42.

12. Autophagy ＊ Physiological Functions of Autophagy
# Autophagy May Be a Guardian of the Genome
Recent studies in ATG gene-deficient immortalized epithelial cells indicate that the autophagic machinery can limit DNA damage and chromosomal instability.
Because these studies used cells with simultaneous defects in DNA checkpoints and apoptosis pathways, it is not yet known whether autophagy
plays a primary function in preventing genomic instability in normal cells.
Failure to control the damage of checkpoint or repair proteins, deregulated turnover of centrosomes, insufficient energy for proper DNA replication and repair, and excessive generation of reactive oxygen species due to inefficient removal of damaged mitochondria are possible alterations that may contribute to genomic instability in autophagy-defective cells
Nat Rev Cancer Dec;7(12):961-7.; Cell Jan 11;132(1):27-42.

13. Autophagy ＊ Physiological Functions of Autophagy
# Autophagy in Life and Death Decisions of the Cell
Autophagy constitutes a stress adaptation pathway that promotes cell survival.
Autophagy is also considered a form of nonapoptotic programmed cell death called “type II” or “autophagic” cell death.
This type of cell death has been historically defined by morphological criteria, but it is now clear that the mere presence of autophagosomes in dying cells is insufficient to distinguish “cell death with autophagy” from “cell death by autophagy.”
Cell Jan 11;132(1):27-42.

14. Autophagy ＊ Autophagy in Disease
Nature 451, (28 February 2008)

15. Autophagy ＊ Autophagy in Disease
# Autophagy and Neurodegenerative Diseases, Muscle Disease and Cardiac Disease
Early reports demonstrating that autophagosomes accumulate in the brains of patients with diverse neurodegenerative diseases, including Alzheimer’s disease, transmissible spongiform encephalopathies, Parkinson’s disease, and Huntington’s disease.
In contrast, more recent studies provide compelling evidence that at least in model organisms autophagy protects against diverse neurodegenerative diseases and that the accumulation of autophagosomes primarily represents the activation of autophagy as a beneficial physiological response or, in the case of Alzheimer’s disease, the consequence of a defect in autophagosomal maturation.
Neuron Aug 29;35(5): ; Cell Jan 11;132(1):27-42.

16. Autophagy ＊ Autophagy in Disease
# Autophagy and Neurodegenerative Diseases, Muscle Disease and Cardiac Disease
Lancet Neurol Apr;6(4):

17. Autophagy ＊ Autophagy in Disease # Autophagy and Liver Disease
The protein quality-control function may be important in the pathogenesis
of the most common genetic cause of human liver disease, α1-antitrypsin deficiency, which is associated with chronic inflammation and carcinogenesis.
Alpha-1-antitrypsin (AT) is the major blood-borne inhibitor of neutrophil proteases.
A point mutation alters the folding pathway and renders the mutant ATZ molecule aggregation-prone.
Cell Jan 11;132(1):27-42.

18. Autophagy ＊ Autophagy in Disease # Autophagy and Cancer
Several tumor suppressor genes involved in the upstream inhibition of TOR signaling, including PTEN, TSC1, and TSC2, stimulate autophagy and, conversely, TOR-activating oncogene products such as class I PI3K and Akt inhibit autophagy.
Autophagy activation represents a cellular attempt to cope with stress induced by cytotoxic agents.
Further in vivo studies are needed with more specific inhibitors of autophagy to determine whether the beneficial effects of blocking a tumor cell survival pathway outweigh the potential detrimental effects of blocking a tumor suppressor pathway.
Cell Jan 11;132(1):27-42.

19. Autophagy ＊ Autophagy in Disease # Autophagy and Aging
Dietary restriction is a potent inducer of autophagy in virtually all species.
C. elegans, autophagy is required for the life-extending effects of dietary restriction; feeding-defective worms do not live longer if treated with siRNA against atg genes.
A similar requirement exists for atg genes in the longevity phenotype of worms with a loss of function mutation in the insulin/IGF-1 signaling pathway.
The mechanism for the decline in autophagy with aging is unknown but, at least in the rodent liver, is thought to involve alterations both in responses to hormonal regulation of autophagy (e.g., glucagon, insulin) and in the degradation of autophagosomes.
Cell Jan 11;132(1):27-42.

20. Autophagy ＊ Autophagy in Disease # Autophagy and Aging
Science Sep 5;301(5638): ; Nature Nov 9;408(6809):

21. Autophagy ＊ Autophagy in Disease
# Autophagy in Infection, Immunity, and Inflammatory Diseases
The autophagy pathway degrades intracellular pathogens, and delivers microbial genetic material and antigens to the necessary cellular compartments for activation of innate and adaptive immunity.
The autophagic sequestration of viral components can also fuel MHC class II
presentation of endogenous antigens11 and the production of type I interferons (IFNs) in response to Toll-like receptor 7 (TLR7) signalling.
The autophagy provides apoptotic cells with signals to ensure their clearance
during programmed cell death.
Cell Jan 11;132(1):27-42.

22. Autophagy
Nat Rev Immunol Oct;7(10):

23. Autophagy ＊ Control of Autophagy
# Regulation of Autophagy by the PI3K/Akt/mTOR Pathway
Growth factors activate receptor tyrosine kinases (RTKs), which then stimulate two key signal transducing components: the small GTPase Ras and the phosphatidylinositol 3-kinase (PI3K). Ras and PI3K converge to activate mTOR for stimulating cell growth and for inhibiting autophagy.
Nature May 25;441(7092): ; Cell Death and Differentiation (2009) 16, 87–93

24. Autophagy ＊ Control of Autophagy
# Regulation of Autophagy by the PI3K/Akt/mTOR Pathway
Cancer Cell Jul;10(1):51-64.; Nature Feb 28;451(7182):

25. Autophagy ＊ Control of Autophagy
# Regulation of Autophagy by Bcl-2 Family Proteins
Antiapoptotic proteins such as Bcl-2, Bcl-XL, Bcl-w and Mcl-1 can inhibit autophagy.
Proapoptotic BH3-only proteins from the Bcl-2 family, such as BNIP3L, Bad, Noxa, Puma, BimEL and Bik, stimulate autophagy.
Nat Rev Mol Cell Biol Sep;8(9): ; Cell Death and Differentiation (2009) 16, 87–93

26. Autophagy ＊ Control of Autophagy # Regulation of Autophagy by p53
p53 has a dual function in the control of autophagy.
On the one hand, nuclear p53 can induce autophagy through transcriptional effects. On the other hand, cytoplasmic p53 may act as a master repressor of autophagy.
How this latter effect is achieved in mechanistic terms is not clear yet
Cell Death and Differentiation (2009) 16, 87–93

27. Autophagy ＊ Control of Autophagy # Regulation of Autophagy by p53
Nat Cell Biol Jun;10(6): ; Cell Death and Differentiation (2009) 16, 87–93

28. Autophagy ＊ Control of Autophagy # Regulation of Autophagy by DAPK
DAPK-1 also induces autophagy and apoptosis, through independent mechanisms.
DAPK-1 can activate the p53 system, suggesting that transcriptional programs influenced by DAPK1 might also affect the propensity of cells to undergo autophagy.
Cell Death and Differentiation (2009) 16, 87–93

29. Autophagy ＊ Control of Autophagy
# Deficient Autophagy as a Mechanism of Oncogenesis
The monoallelic deletions of beclin 1 in human cancer likely contribute tumorigenesis,
Cell Death and Differentiation (2009) 16, 87–93

30. Autophagy ＊ Control of Autophagy
# Deficient Autophagy as a Mechanism of Oncogenesis
Tumor suppression may be a shared property of several distinct autophagy proteins that act at different steps in the pathway.
Cell Death and Differentiation (2009) 16, 87–93

31. Autophagy ＊ Control of Autophagy
# Enhanced Autophagy as a Mechanism of Tumor Cell Survival
Cell Death and Differentiation (2009) 16, 87–93