The Role of Autophagy in Mammalian Development: Cell Makeover Rather than Cell Death

Dulbecco Telethon Institute at the Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
Developmental Cell (Impact Factor: 9.71). 10/2008; 15(3):344-57. DOI: 10.1016/j.devcel.2008.08.012
Source: PubMed

ABSTRACT Autophagy is important for the degradation of bulk cytoplasm, long-lived proteins, and entire organelles. In lower eukaryotes, autophagy functions as a cell death mechanism or as a stress response during development. However, autophagy's significance in vertebrate development, and the role (if any) of vertebrate-specific factors in its regulation, remains unexplained. Through careful analysis of the current autophagy gene mutant mouse models, we propose that in mammals, autophagy may be involved in specific cytosolic rearrangements needed for proliferation, death, and differentiation during embryogenesis and postnatal development. Thus, autophagy is a process of cytosolic "renovation," crucial in cell fate decisions.

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Available from: Francesco Cecconi, Dec 24, 2014
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    • "The autophagy-lysosomal pathway (ALP) is an evolutionarily conserved catabolic process by which the cell removes and recycles complexes, protein aggregates and damaged organelles [24]. Often observed as a mechanism to address starvation and reduce energy output, autophagy can also contribute to cellular differentiation, growth control, defense from xenobiotics, as well as general housekeeping and maintenance [25]. Thus, autophagy is generally thought of as a survival mechanism. "
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    ABSTRACT: The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained health span. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extend human health span and lifespan. The ubiquitin-proteasome and autophagy-lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared with shorter-lived rodents. Using a 2-D PAGE proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan and may contribute to the extraordinary health span of these rodents. The potential of augmenting human health span via activating the proteostasis network will require further studies. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 08/2015; 1852(10 Pt A). DOI:10.1016/j.bbadis.2015.08.002 · 4.66 Impact Factor
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    • "Additionally, it has been observed that mTOR inhibition induces a variety of processes, including macroautophagy (hereafter referred to as autophagy) (Loewith et al., 2002). This evolutionary conserved process is normally responsible for protein turnover and the elimination of damaged organelles and cytoplasmic components in order to maintain homeostasis in the cell (Cecconi and Levine, 2008). Under pathological conditions such as cancer, autophagy is considered to serve as a pro-survival mechanism (Chen and Karantza-Wadsworth, 2009). "
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    ABSTRACT: Cisplatin is used as a cytotoxic agent for the management of cervical cancer. However, the severity of the side-effects limits the use of this drug, particularly at high doses. Resistance to cisplatin is often attributed to a disruption in the normal apoptotic response via aberrant activation of pathways such as the mTOR pathway. Here we assess the role of mTOR and its effect on cell death sensitization and autophagy in response to a low concentration of cisplatin in cervical cancer cells. Additionally we measured the expression profile of mTOR in normal, low- and high-grade squamous intraepithelial (LSIL and HSIL) lesions and cancerous tissue. An in vitro model of cervical cancer was established using HeLa and CaSki cells. mTOR protein expression as well as autophagy-related proteins were evaluated through Western blotting. Inhibition of mTOR was achieved with the use of rapamycin and RNA silencing. A low concentration of cisplatin administered as a single agent induces autophagy, but not apoptosis. Cisplatin cytotoxicity was greatly enhanced in cancer cells when mTOR had been inhibited prior to cisplatin treatment which was likely due to autophagy being increased above cisplatin-induced levels, thereby inducing apoptosis. Cervical tissue samples revealed an increase in mTOR protein expression in LSIL and carcinoma tissue which suggests a change in autophagy control. Our data suggest that utilising a lower dose of cisplatin combined with mTOR inhibition is a viable treatment option and addresses the challenge of cisplatin dose-dependent toxicity, however future studies are required to confirm this in a clinical setting. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology 07/2015; 335. DOI:10.1016/j.tox.2015.07.010 · 3.62 Impact Factor
    • "During periods of exercise and physical activity, the increased frequency and amplitude of intracellular calcium spikes can substantially contribute to cellular protein turnover and removal of dysfunctional or damaged organelles [2]. Eukaryotic cells degrade long-lived proteins, organelles, and bits of cytoplasm via the lysosome-dependent mechanism of macroautophagy, here after referred to as autophagy [3] [4]. Autophagy is a highly conserved and tightly regulated process, which involves the formation of double membrane vesicles (autophagosomes) around molecules that have been targeted for degradation [5]. "
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    ABSTRACT: Caffeine has been shown to promote calcium-dependent activation of AMP-activated protein kinase (AMPK) and AMPK-dependent glucose and fatty acid uptake in mammalian skeletal muscle. Though caffeine has been shown to promote autophagy in various mammalian cell lines it is unclear if caffeine-induced autophagy is related to the calcium-dependent activation of AMPK. The purpose of this study was to examine the role of calcium-dependent AMPK activation in regulating caffeine-induced autophagy in mammalian skeletal muscle cells. We discovered that the addition of the AMPK inhibitor Compound C could significantly reduce the expression of the autophagy marker microtubule-associated protein 1 light chain 3b-II (LC3b-II) and autophagic vesicle accumulation in caffeine treated skeletal muscle cells. Additional experiments using pharmacological inhibitors and RNA interference (RNAi) demonstrated that the calcium/calmodulin-activated protein kinases CaMKKβ and CaMKII contributed to the AMPK-dependent expression of LC3b-II and autophagic vesicle accumulation in a caffeine dose-dependent manner. Our results indicate that in skeletal muscle cells caffeine increases autophagy by promoting the calcium-dependent activation of AMPK.
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