here is some information about autophagy, how it happend, when it happend and it's mechanism.
and some information about it's effect on cancer and some disorders.
2. Contents
■ Introduction
■ What happened in Autophagy?
■ History
■ Lysosome
■ Different type of autophagy
■ Mechanism of autophagy
■ Autophagy and cancer
■ References
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3. Introduction
■ Autophagy is a self-degradative process that is important for balancing sources of
energy at critical times in development and in response to nutrient stress.
■ The liver is rich in lysosomes and possesses high levels of metabolic-stress-induced
autophagy.
■ Autophagy regulated by concentrations of hormones and amino acids.
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4. What happened in autophagy?
1. Induction by activation of signaling molecules: Protein kinases (including the mTOR
complex 1) that relay information about the metabolic status of the cell, become
activated and signal to the autophagic machinery.
2. Nucleation and extension of a delimiting membrane into a crescent-shaped cup:
Membrane vesicles, characterized by the presence of ATG9, the only transmembrane
protein involved in the process, are recruited to an assembly site, where they nucleate
autophagosome formation. ATG9 is not incorporated into the autophagosome: a
retrieval pathway must remove it from the assembling structure.
3. Closure of the membrane cup around the target to form a sealed double- membrane-
enclosed autophagosome.
4. Fusion of the autophagosome with lysosomes, catalyzed by SNAREs.
5. Digestion of the inner membrane and the lumenal contents of the autophagosome
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5. ATG (AuTophaGy related proteins)
■ First time described in yeasts.
■ They have some homologs in
mammalians.
■ They have different roles such as
enzyme, signaling, transporter,
scaffold, ubiquitin-like protein,
etc.
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6. History
■ First time observed by Keith R. Porter and his student Thomas Ashford at the
Rockefeller Institute in 1962 soon after the discovery of lysosomes in rat liver.
■ They called this autolysis after Christian de Duve and Alex B. Novikoff.
■ A new era of autophagy research began in 1990s when several groups of scientists
independently discovered autophagy-related genes using the budding yeast.
■ In 1999, a landmark discovery connecting autophagy with cancer was published by
Beth Levine’s group
■ In 2005, Daniel J Klionsky launched “Autophagy”, a scientific journal dedicated to this
field.
■ The first Keystone Symposia on autophagy was held in 2007 at Monterey
■ 6426 article were published about it from 2007 until 2012.
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7. Nobel prize 2016
■ The 2016 Nobel Prize in Physiology or
Medicine was awarded toYoshinori Ohsumi.
■ A Japanese cell biologist
■ Ohsumi is a professor at Tokyo Institute of
Technology's Institute of Innovative
Research.
■ The Kyoto Prize for Basic Sciences in 2012.
■ The Gairdner Foundation International Award
in 2015.
■ The Wiley Prize in Biomedical Sciences in
2016.
■ The 2017 Breakthrough Prize in Life Sciences
for his discoveries of mechanisms for
autophagy.
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8. Lysosome
■ A lysosome is a membrane-bound
organelle found in nearly all animal cells.
■ Discovered by Christian de Duve in 1952.
■ 80-90A° membrane, riched by
phosphatidil choline.
■ Marker protein is acid phosphatase.
■ HaveV-type ATP dependent proton pump.
■ Signal of lysosome proteins is Man-6-P.
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9. Why lysosome’s membrane is stable?
■ It has 2 reasons:
– Glycoproteins at innermembrane
– Proton pump make pH 2 near membrane
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16. Different type of autophagy
■ Micro-autophagy
■ Macro-autophagy
■ Chaperone-mediated autophagy
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17. Microautophagy
■ Some proteins and organelles have directly join
to lysosome, vacuole (plants) or late endosome.
■ Generally is a non-selective process but in some
cases is selective:
– micropexophagy
– Piecemeal microautophagy of the nucleus
– micromitophagy
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21. Chaperone-mediated autophagy
■ Some special cytosolic proteins have a
specific guide motif (KFERQ) with hsc 70
and other chaperones attach to lysosomal
membrane.
■ That guide motif attach them to LAMB-
A2 receptor protein at the surface of
lysosomes and transport them into
lysosome with LAMB-A2 dependent
transporter.
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26. mTOR (mammalianTarget of Rapamycin)
■ TOR regulates induction of autophagy in cooperation with two other nutrient sensing
pathways, that is, protein kinaseA and SCh9.
■ In mammals, mTOR appears to regulate autophagy in similar way to the yeast.
■ thatmammalian target of rapamycin (mTOR) acts as a negative regulator, and the
extent of autophagy is regulated by proteins upstream of mTOR signaling, including
PTEN, PDK1,Akt, andTSC1/2.
■ For example, PTEN andTSC1/2 positively regulate autophagy, whereas Akt inhibits it.
■ Downstream targets of mTOR, including elongation factor-2 kinase, and S6kinase,
have been shown to regulate autophagy
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28. P53
■ The fact is that p53 suppressor is mutated in approximately 50% of human cancers and
induces autophagy.
■ p53 can be a positive or negative regulator of autophagy depending on subcellular
localization and type of stress.
■ It has been reported that P53 functions as critical mediator for damage-induced
apoptosis and has been shown to induce autophagy in DRAM- (Damage-regulated
autophagy modulator-) dependent manner to execute a full cell death in human
cancer cell lines.
■ DRAM is a lysosomal integral membrane protein, and a direct target of p53-induces
macroautophagy and helps in accumulation of autophagosomes.
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31. Problem in autophagy
■ Degradative disorders
■ Metabolic syndromes
■ Aging
■ Infection disease
■ Self immune problems
■ Diabetes
■ Cardiomyopathy
■ Cancer
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32. Autophagy and Cancer
■ However, data on autophagy genes is more limited
than apoptosis. In cancers, ATG2, ATG5, ATG9, ATG12,
and UVRAG genes have been reported to be mutated
with microsatellite instability.
■ The Atg6 (Beclin1) gene is deleted in some cancers.
■ The UVRAG mutated binds with Beclin-1 in gastric and
colorectal cancers with microsatellite instability.
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33. References
■ Badadani, M., 2012. AutophagyMechanism, Regulation, Functions, and Disorders. Cell
Biology,Volume 2012 , p. 11.
■ Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith
Roberts, PeterWalter, 2015. molecular biology of the cell. 6 ed. NewYork(NewYork):
Garland Science,Taylor & Francis Group.
■ Gregor M. Balaburski, Robert D. Hontz and Maureen E. Murphy, 2010. p53 and ARF:
unexpected players in autophagy.Trends in Cell Biology , 20(6), p. 363–369.
■ Harvey Lodish,Arnold Berk, Chris A. Kaiser, Monty Krieger, Anthony Bretscher, Hidde
Ploegh,AngelikaAmon, Kelsey C. Martin, 2016. Molecular Cell Biology. 8 ed. NewYork:
Katherine Ahr Parker.
■ Mizushima, N., 2007.Autophagy process and function. Genes development, 15(21), pp.
2861-2873..
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