Genetics of type 2 diabetes barroso,gl 350 mercedes used,symptoms and treatment of diabetes mellitus oms,diabetes symptoms of high blood sugar level - Tips For You


In an interview Kirt Tyson, a former type I diabetic, revealed that his diet was completely raw, with no fruits.
In addition to going raw and eliminating sugar from your diet, you must switch to raw milk or its alternatives. Fig leaves are best known for treating diabetes, but there are many other uses for them They can be used in homemade remedies from treating diabetes to treating bronchitis, genital warts, liver cirrhosis, high blood pressure, skin problems and ulcers. The Diabetes Forum - find support, ask questions and share your experiences with 209,001 people. This section looks at the different systems in the body, how the bodya€™s organs work and how they can be affected by diabetes. The pancreas is recognised by many of us as having an effect on blood sugar levels but there are many more organs which play a role in diabetes. Choose a system by hovering over it and see the role that different organs, hormones and responses play in ensuring the body functions.
Type 1 diabetes is the result of an autoimmune response, whereby the body's immune system attacks its own insulin producing cells. The effect of diabetes on the respiratory system is less significant than it is for other organ systems.
Bones behave as an endocrine organ by releasing hormones which help improve sensitivity to insulin.
Find support, ask questions and share your experiences with 209,001 members of the diabetes community.
10 week (free) low-carb education program developed with the help of 20,000 people with T2D and based on the latest research.
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One special case of genetics that doesn’t follow by the Mendelian principles of inheritance is the sex-linked genes. Another special case is the polygenic inheritance, which happens when one characteristic is controlled by two or more genes. Discuss the evolutionary arms race that exists between a planet of viruses and our immune system. Cell homeostasis depends on the balance between the production and destruction of macromolecules and organelles. The role of LC3 and of other members of the mammalian Atg8 family (GABARAPs) remains to be fully elucidated. DRAM (Damage-regulated autophagy modulator) encodes a 238-amino acid protein which is conserved through evolution, but has no ortholog in yeast (Crighton et al., 2006). ATPases associated with various cellular activity proteins (AAA ATPases) are a family of proteins broadly engaged in intracellular membrane fusion (White and Lauring, 2007). Signaling segments acting upstream of mTORC1 and mTORC2 that regulate autophagy have been discussed in recent reviews that the reader can consult for more information (Codogno and Meijer, 2005; Meijer and Codogno, 2009).
Beclin 1 is one of the essential components involved in autophagosome formation, and its level usually increases during autophagy.
Autophagosome formation occurs at a basal rate in most cells and controls the quality of the cytoplasm by initiating the elimination of protein aggregates and of damaged organelles (Ravikumar et al., 2010b) (Figure 3).
Stimulation of autophagy during periods of starvation is an evolutionarily-conserved response to stress in eukaryotes (Yang and Klionsky, 2010). The pioneering work of Bergamini and colleagues in the field of autophagy (Yang and Klionsky, 2010) suggested that its stimulation during calorie restriction may contribute to extending lifespan in the rat. As mentioned above, basal autophagy is important as a housekeeping process to prevent the deposition of aggregation-prone proteins in the cytoplasm (Figure 3). In infectious diseases, autophagy is involved in the elimination of intracellular pathogens (bacteria, viruses and parasites), and thus contributes to the innate immunity (Levine and Deretic, 2007; Virgin and Levine, 2009). Cancer is frequently associated with defects in autophagy, but the role of autophagy in cancer is clearly complex, because autophagy is also required in the later stages of tumor progression to enable tumor cells to cope with metabolic stress (caused by limited supplies of oxygen and nutrients) (Levine, 2007). Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D, Lullmann-Rauch R, Janssen PM, Blanz J, von Figura K, Saftig P. Ishihara N, Hamasaki M, Yokota S, Suzuki K, Kamada Y, Kihara A, Yoshimori T, Noda T, Ohsumi Y. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM.
Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y. Eskelinen EL, Schmidt CK, Neu S, Willenborg M, Fuertes G, Salvador N, Tanaka Y, L?llmann-Rauch R, Hartmann D, Heeren J, von Figura K, Knecht E, Saftig P.
Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T, Pierron G, Codogno P, Kroemer G. Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E, Gotow T, Peters C, von Figura K, Mizushima N, Saftig P, Uchiyama Y. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas G. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B.
Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O'Kane CJ, Brown SD, Rubinsztein DC. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E. Djavaheri-Mergny M, Amelotti M, Mathieu J, Besan‡on F, Bauvy C, Souquere S, Pierron G, Codogno P.
Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier-Hayes L, Fitzgerald P, Guio-Carrion A, Waterhouse NJ, Li CW, Mari B, Barbry P, Newmeyer DD, Beere HM, Green DR.
Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, Hirsch JA, Stein R, Pinkas-Kramarski R.
Fabre C, Carvalho G, Tasdemir E, Braun T, Ades L, Grosjean J, Boehrer S, Metivier D, Souquere S, Pierron G, Fenaux P, Kroemer G. Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Maler›d L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A. IRS1-Independent Defects Define Major Nodes of Insulin Resistance Cell Metabolism, 7, 421-433, (07 May 2008)Kyle L. Intra-islet insulin suppresses glucagon release via GABA-GABA(A) receptor system.Cell Metabolism.
Increased insulin sensitivity and hypoinsulinemia in APS knockout mice Diabetes 52, 2657-2665 (2003)Asako Minami, Masanori Iseki, Kazuhiro Kishi, Miao Wang, Makoto Ogura, Noboru Furukawa, Sanae Hayashi, Mizuki Yamada, Toshiyuki Obata, Yukari Takeshita, Yutaka Nakaya, Yoshimi Bando, Keisuke Izumi, Shonna A. Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissueNature Genetics.
Gq-coupled receptors transmit the signal for GLUT4 translocation via an insulin-independent pathwayJ. Platelet-derived growth factor triggers translocation of the insulin-regulatable glucose transporter (type 4) predominantly through phosphatidylinositol 3-kinase binding sites on the receptorProc. Direct demonstration of insulin-induced GLUT4 translocation to the surface of intact cells by insertion of a c-myc epitope into an exofacial GLUT4 domainJ. Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin- and antibody-stimulated glucose uptake and receptor kinase activityProc. Share this empowering narrative on your social network of choice and ask others to do the same.
Click on a body system or body part and see the role that organs, hormones and responses play in ensuring the body functions and how diabetes can affect them. This is a special case, because in Mendel’s law of independent assortment, he claims that genes are inherited separately from each other.
There are two major systems in eukaryotic cells that degrade cellular components: the ubiquitin proteasome system (UPS) and the lysosome. Autophagy is initiated by the formation of a double membrane-bound vacuole known as the autophagosome. Regulation of autophagy and its relationship with signaling molecules and apoptotic mediators. However, a recent study shows that LC3s and GABARAPs are involved in different steps of autophagosome biogenesis (Weidberg et al., 2010). The endosomal sorting complex required for transport (ESCRT) mediates the biogenesis of MVB and the sorting of proteins in the endocytic pathway (Raiborg and Stenmark, 2009).
Vacuolar ATPases (v-ATPase) are ubiquitous, multi-subunit proteins located in the acidic compartment (Forgac, 2007). N-ethylmaleimide sensitive factor (NSF) is an AAA ATPase, which binds to SNARE complexes and utilizes ATP hydrolysis to disassemble them, thus facilitating SNARE recycling. In this section we would like to focus on signaling pathways with identified targets in the molecular machinery of autophagosome formation.
Many signals, including growth factors, amino acids, glucose, and energy status, are integrated by the kinase mTOR (Kim et al., 2002). As discussed above,ULK1, Atg13 and FIP200 form a stable complex that signals to the autophagic machinery downstream of mTORC1. Autophagy can also be induced via an mTOR-independent pathway by lowering myo-inositol 1,4,5-trisphosphate (IP3) levels (Sarkar et al., 2005). The function of Atg proteins in autophagy can be regulated not only by protein-protein interactions and phosphorylation, but also by oxidation, acetylation, and proteolytic cleavage.
The sphingolipid ceramides have been shown to increase the expression of Beclin 1 in human cancer cell lines (Scarlatti et al., 2004). The NF-κB transcription factor, which plays a plethoric role in inflammation, immunity and cancer (Karin, 2006), has also been implicated in regulating autophagy.
E2F transcription factors are known to be involved in cellular proliferation, but also in DNA repair, differentiation and development (DeGregori and Johnson, 2006).
HIF-1 (hypoxia-inducible factor-1) is a transcription factor, which regulates the transcription of hundred of genes in response to hypoxia (Manalo et al., 2005).
Recently the bHLH-leucine zipper transcription factor TFEB has been shown to control lysosomal biogenesis and function. For example, in HBV (hepatitis B virus)-infected hepatocytes, the HBV x protein increases autophagy by upregulating the expression of Beclin 1 (Tang et al., 2009). Under starvation conditions, the degradation of proteins and lipids allows the cell to adapt its metabolism and meet its energy needs (Figure 3). The pre-implantation period after oocyte fertilization is dependent on autophagic degradation of components of the oocyte cytoplasm (Tsukamoto et al., 2008). Recent data have shown that the induction of autophagy increases longevity in a large panel of species (Eisenberg et al., 2009).
Several neurodegenerative diseases, including Huntington's, Alzheimer's and Parkinson's diseases, are characterized by the accumulation of such protein aggregates in the brain (Ravikumar et al., 2010b). Defective hepatic autophagy probably makes a major contribution to insulin resistance and to predisposition to type-2 diabetes and obesity (Yang et al., 2010). The link between autophagy and cancer is further strengthened by the fact that several of the proteins involved in regulating autophagy are known to be tumor suppressor genes or oncoproteins (Morselli et al., 2009).
Kevin Woodford explains how the type of milk we drink directly reflects the high incidence of many diseases, including diabetes and cancers. These genes carry the traits that determine if the offspring is male or female, and that genes that are carried by both chromosomes are known as sex-linked genes. Some examples of polygenic inheritance can be seen in human, such as height, weight, and skin color.
The UPS only degrades proteins, mainly short-lived proteins that have to be tagged by ubiquitin to be recognized by the proteasome (Ciechanover et al., 2000).
In the presence of amino acids, growth factors and energy, the mTOR complex 1 (mTORC1) represses autophagy by inhibiting the kinase activity of ULK1.


The kinase activity of ULK1 is controlled by the kinase mTOR in the mTORC1 complex sensitive to rapamycin (Hosokawa et al., 2009). LC3s mediate the elongation of the autophagic membrane, and GABARAPs mediate a downstream event probably associated with the closure of the autophagosome membrane. Seglen (reviewed in Fengsrud et al., 2004) for the vacuole that results from the fusion of an autophagosome with an endosome. Autophagosome maturation is dependent on interactions with class C Vps proteins and UVRAG (Liang et al., 2008). Autophagic degradation has been shown to be impaired in hepatocytes isolated from LAMP-2 deficient mice (Tanaka et al., 2000). Inhibition of the activity of v-ATPase by bafilomycin A1 or concanamycin A blocks the lysosomal pumping of H+ and consequently inhibits lysosomal enzymes, which are active at low pH. In yeast mutants lacking sec18 (the yeast homolog of NSF), autophagosomes are formed, but dot not fuse with the vacuole (Ishihara et al., 2001). We will also discuss the role of signaling pathways and transcription factors in the regulation of the expression of genes involved in controlling autophagy.
Activation of AMPK inhibits mTOR-dependent signaling, by interfering the activity of the GTPase Rheb, and protein synthesis (Meijer and Codogno, 2004). This effect can be achieved pharmacologically with drugs such as lithium or L-690 330, which disrupt the metabolism of inositol by inhibiting inositol monophosphatase (IMP). Elazar and colleagues (Scherz-Shouval et al., 2007) have reported that the oxidation of a cysteine residue near the catalytic site of Atg4A and Atg4B is required during starvation-induced autophagy.
E2F1 has been shown to bind to the promoter of Becn1, although an effect of E2F1 on Beclin 1 expression remains to be demonstrated (Weinmann et al., 2001). Recently Zhang et al have demonstrated that hypoxia-induced mitochondrial autophagy via HIF-1 mediated induction of Bnip3 (Zhang et al., 2008). FoxO proteins are phosphorylated by Akt, which renders them inactive in the presence of growth factors.
When p53 is activated by cellular stress, p53 accumulates in the cell nucleus, where it transactivates several autophagy-modulating genes including Dram (damage-regulated autophagy modulator) and Tigar (TP53-induced glycolysis and apoptosis regulator). They showed that miR-30a targets Beclin 1 mRNA, and down-regulates the expression of Beclin 1.
The stimulation of autophagy plays a major role at birth to maintain energy levels in various tissues after the maternal nutrient supply via the placenta ceases (Kuma et al., 2004).
Autophagy remodeling of the cytoplasm is involved during the differentiation of erythrocytes, lymphocytes and adipocytes (Ravikumar et al., 2010b). The antiaging effect of autophagy probably depends, at least in part, on its quality control function that limits the accumulation of aggregation-prone protein and damaged mitochondria. The physiological role of basal autophagy is to clean the cytoplasm of damaged organelles and protein aggregates. As a protective measure, the stimulation of autophagy limits the accumulation of toxic products and protects neurons against degeneration. TLR ligands induce autophagy to promote the delivery of infecting pathogens to the lysosomes (Levine and Deretic, 2007). The once debilitating disease can be treated by eating a raw diet and making some life-changing decisions. While men normally have an X and Y combination of sex chromosomes, women have two X chromosomes.
For example in skin color, there isn’t a single gene for brown or white skin but a mixture of multiple genes and their interaction.
The lysosomal system is responsible for degrading macromolecules, including proteins, and for the turnover of organelles by autophagy (Mizushima et al., 2008). The late stage of autophagy depends on molecules that regulate the maturation of autophagosomes, including their fusion with endosomes and lysosomes, as well as on the acidification of the autophagic compartments, and the recycling of metabolites from the lysosomal compartment (Figure 1). Therefore, Beclin 1 regulates both the formation of autophagosomes (via its interaction with Atg14L) and the maturation of autophagosomes (via its interaction with UVRAG and Rubicon). However, no defect in autophagy was observed in LAMP-2 deficient mouse fibroblasts (Eskelinen et al., 2004). DRAM may regulate late stages of autophagy, but surprisingly it also controls the formation of autophagosomes (Crighton et al., 2006). However, we do not know whether the ATPase activity of NSF plays a role in the later stages of autophagy in mammalian cells.
The final stage of autophagy is the efflux of metabolites generated by the lysosomal degradation of macromolecules into the cytosol (reviewed in Lloyd, 1996). Interestingly, FoxO3 has been shown to stimulate autophagy in muscle cells by increasing the transcription of several genes involved in autophagy (see below) (Mammucari et al., 2007). This is consistent with the switch off of ATP-dependent processes (Hardie, 2004) during period of energy crisis. Rubinsztein and coworkers found that L-type Ca2+ channel antagonists, the K+ATP channel opener, and Gi signaling activators all induce autophagy (Williams et al., 2008). During starvation, the deacetylation of Atg5, Atg7, LC3 and Atg12 is important to stimulate autophagy. More recently, the activation of E2F1 has been shown to induce autophagy by upregulating the expression of the autophagy genes Map1lc3, Ulk1, Atg5 and Dram (we have adopted the nomenclature Map1lc3 for the gene encoding LC3) (Polager et al., 2008). When Akt is repressed, FoxO proteins are translocated into the nucleus, bind to DNA, and transactivate its target genes (Salih and Brunet, 2008).
DRAM stimulates the accumulation of autophagosomes, probably by regulating autophagosome-lysosome fusion to generate autophagolysosomes (Crighton et al., 2006). TFEB not only controls the expression of lysosomal proteins, it also regulates the autophagy transcription program during starvation (Settembre et al., 2011).
During the unfolded protein response, triggered by hypoxia, the transcription factors ATF4 and CHOP, which are regulated by PERK, increase the expression Map1lc3b and Atg5, respectively (Rouschop et al., 2010). The transcription factor implicated has not been identified, but it has been shown that in human monocytes the effect of Vitamin D3 is mediated via cathelicidin. Moreover, starvation-induced autophagy is cytoprotective by blocking the induction of apoptosis upstream of mitochondrial events (Boya et al., 2005). Autophagy is crucial for the homeostasis of immune cells, and contributes to the regulation of self-tolerance (Nedjic et al., 2008). Calorie restriction stimulates autophagy via the activation of the deacetylase sirtuin-1 (Morselli et al., 2010). Remarkably, autophagy facilitates effective glucose uptake and glycolytic flux in Ras-transformed cells (Lock et al., 2011).
278:28312-28323(2003)Toshiyuki Obata, Takashi Katome, Rie Matsushima, Norihisa Masuyama, Lewis C. Not only can you go raw, but you can also use eight natural herbs and remedies to survive diabetes. Continuing to eat healthy for the rest of your life ensures that you too can be free from any reoccurrence of this disease. This means that X-linked recessive traits are usually displayed in the phenotype of men, as there aren’t corresponding genes in the Y chromosome.
In polygenic inheritance, the outcome is unpredictable, and the more varied the parent genes are, then the more varied the outcome is. The boundary membrane arises from a single membrane, known as the phagophore or isolation membrane (reviewed in Yang and Klionsky, 2010) (Figure 1). These steps are of a fundamental importance for the flux (defined here as extending from the cargo sequestration step to that of its lysosomal degradation) of material through the autophagic pathway (Codogno and Meijer, 2005). Interestingly, Rab11 is required for the fusion of autophagosomes and multivesicular bodies (MVB) during starvation-induced autophagy in the erythroleukemic cell line K562 (Fader et al., 2008).
The Hrs protein (hepatocyte growth factor-regulated tyrosine kinase substrate) plays a major role in endosomal sorting upstream of ESCRT complexes (Raiborg and Stenmark, 2009). The mammalian homologue of Vt1, Vti1b, may be involved in a late stage of autophagy, because the maturation of autophagic vacuoles is delayed in hepatocytes isolated from mice in which Vti1b has been deleted (Atlashkin et al., 2003). A blockade in the later stage of autophagy only occurs in fibroblasts that are deficient for both LAMP-1 and LAMP-2. This suggests the possibility of a new paradigm in which feedback signals from the lysosomes control the early stages of autophagy. Overall, the resulting effect of the inhibition of v-ATPase is to interrupt the autophagic flux as determined by the lysosomal inhibition of autophagic cargo.
Nevertheless the activity of NSF is attenuated during starvation, which provides a possible explanation for the slow fusion between autophagosomes and lysosomes observed when autophagy is induced by starvation (Fass et al., 2006). Atg22 has recently been identified as a permease that recycles amino acids from the vacuole in S. Under starvation conditions or in response to rapamycin treatment, mTORC1 dissociates from the ULK1 complex, resulting in the activation of ULK1. The acetylation is dependent on the activity of p300 (Lee and Finkel, 2009), and the deacetylation is probably under the control of the histone deacetylase sirtuin 1 (Lee et al., 2008). They also showed that c-Jun controls the transcription of Becn1 (we have adopted this nomenclature for the gene encoding Beclin 1), and the induction of autophagic cell death in response to ceramide. The E2F1-mediated induction of Map1lc3, Ulk1 and Dram is direct (interaction with the promoter), whereas the up-regulation of the expression of Atg5 is indirect.
TIGAR, through its fructose 2, 6-bisphosphatase function, can modulate the glycolytic pathway and indirectly contribute to the fall in the intracellular level of ROS (Bensaad et al., 2006).
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multifunctional enzyme known to play a role in glycolysis as well as having other less well-understood roles such as transcriptional coactivation, has also been shown to upregulate the transcription of Atg12 to protect cells against caspase-independent cell death (Colell et al., 2007). The stimulation of autophagy during periods of starvation plays a major role in many tissues, but with some exceptions, such as the brain, in providing nutrients for cell metabolism, for the biosynthesis of macromolecules, and to maintain the level of ATP. Autophagy is involved in the clearance of aggregation-prone proteins in muscle diseases, including limb girdle muscular dystrophy type 2B, Miyoshi myopathy, and sporadic inclusion body myositis. Recently polymorphisms of the genes that encode and IRGM, two autophagy genes essential for the elimination of intracellular pathogens, have been associated with Croh's disease, a chronic inflammatory bowel disease (Virgin and Levine, 2009).
Moreover, the loss of autophagy in Ras-transformed cells is associated with reduced oxygen consumption and lower levels of the tricarboxylic acid (TCA) intermediate (Guo et al., 2011). USA 92, 1077-1081 (1995)Seika Kamohara, Hideki Hayashi, Mikio Todaka, Fumihiko Kanai, Kazuo Ishii, Takanobu Imanaka, Jaime A.
USA 84, 704-708 (1987)Yousuke Ebina, Eiichi Araki, Masato Taira, Fumio Shimada, Masataka Mori, Charles S. It also explains why females are usually the carrier of X-linked genes, but don’t display them in their own phenotypes, as they have two sets of X chromosomes which could mask the phenotype. Though the individual genes follow the Mendelian patterns of inheritance, the traits do not, because they are controlled by the interaction of more than one gene.
The term "autophagy" was coined by Christian de Duve soon after his discovery of lysosomes (see reference Klionsky, 2007 for an historical view of autophagy). Once completed, autophagosomes receive inputs from the endocytic pathway, and thus acquire acidic and degradative capacities.
In most cases, once the autophagosome has been formed it receives input from the endocytic pathway (early and late endosomes and multivesicular bodies-MVB).
These findings suggest that specific membrane-bound compartment fusion processes during the maturation of autophagosomes engage different sets of Rab proteins, and possibly associated cohort proteins. Hrs contains a FYVE domain that binds specifically to PtdIns3P, and facilitates the maturation of autophagosomes (Tamai et al., 2007).
More recently, Colombo and colleagues (Fader et al., 2009) have reported that VAMP3 and VAMP7, two v-SNAREs, control the fusion between autophagosomes and MVB and fusion of amphisomes with lysosomes, respectively. The differences in the autophagic activity observed between hepatocytes and fibroblasts may be responsible for the cell type-specific effects of LAMP-1 and LAMP-2 depletion (Eskelinen, 2005). Suppressor of K+ transport growth defect 1 (SKD1-Vps4), another AAA ATPase protein, is required for the maturation of autophagosomes (Nara et al., 2002) in mammalian cells. Activated ULK1 autophosphorylates, and also phosphorylates both Atg13 and FIP200 to initiate autophagy (Hosokawa et al., 2009). These data also suggest that insults that elevate intracytosolic Ca2+ (such as excitotoxicity) inhibit autophagy, thus retarding the clearance of aggregate-prone proteins. Activation of JNK, resulting in the upregulation of Beclin 1 expression, has also been reported in the autophagic cell death of human colon cancer cells induced by the stimulation of the human death receptor 5 (Park et al., 2009). BNIP3 and BNIP3L play important roles in the induction of autophagy by disrupting the interaction of Beclin 1 with Bcl-2 via their BH3 domain.


Recently, the same group showed that TIGAR can also modulate the intracellular ROS level in response to nutrient starvation or metabolic stress, and consequently inhibit autophagy via an mTOR-independent pathway (Bensaad et al., 2009). The reduction of TFEB phosphorylation during starvation triggers its nuclear transport where it activates a transcription program that activates the biogensesis of lysosomes and stimulates autophagy. In several cell lines, deacetylation of these Atg proteins is necessary for autophagy to be stimulated by nutrient deprivation (Lee et al., 2008). Autophagy is involved in an early stage of development (pre-implantation of the fertilized oocyte), and differentiation. Blockade of the autophagic pathway leads to the cardiomyopathy and myopathy of Danon disease (Ravikumar et al., 2010b).
The high basal level of autophagy observed in tumors with Ras mutation is required for cancer cell survival (Yang et al., 2011). One example of this in real life is the hemophilia disease, which is a sex-linked disorder that can slow blood clotting in the blood.
These acidic and degradative vacuoles form single-membrane compartments known as amphisomes (reviewed in Yang and Klionsky, 2010). DFCP1 is located at the Golgi in resting cells, but in response to autophagy stimulation it is recruited to an ER structure known as the omegasome (Axe et al., 2008). This raises the intriguing possibility that PtdIns3P may be required for the formation of the autophagosome and its maturation.
The location of phosphorylation sites, as well as the role played by other members of the ULK family, ULK2 and ULK3, remain to be determined. In a reciprocal manner, the BH3 domain of Beclin 1 can be phosphorylated by death-associated protein kinase (DAPk), which has the effect of reducing its affinity for Bcl-XL (Zalckvar et al., 2009). Both genetic and pharmacological inhibition of the IP3 receptor (IP3R) strongly stimulate autophagy. HIF-1 could also regulate the expression of Beclin 1 and Atg5, probably indirectly although according to a recent report the silencing of HIF-1 in cultured chondrocytes was associated with a reduced level of Beclin 1 (Bohensky et al., 2007).
Expression of a constitutive form of FoxO3 induces autophagy in adult mouse skeletal muscle. So, while DRAM and TIGAR are both transactivated by p53, DRAM promotes autophagy whereas TIGAR inhibits autophagy. TFEB has a broad range of activities, because it controls the activity of genes involved in various different steps of autophagy, including autophagosome formation (Map1lc3, Wipi), cargo recognition (Sqstm1,) and autophagosome fusion with the lysosomal compartment (Uvrag, Vps11, Vps18). It would be interesting to investigate whether this regulation of autophagy is conserved in tissues that preferentially use fatty acids as oxidizable substrates during starvation, where a high level of acetyl-CoA is to be expected. Autophagy declines during aging, and the restoration of autophagy extends life span in various species.
Autophagy is also involved in muscle atrophy but it is unclear whether autophagy has a beneficial effect by promoting survival during catabolic conditions, or a detrimental effect by causing atrophy. In these tumors, autophagy certainly constitutes an Achilles heel that could be used in the fight against cancer. However the term "autophagy" also embraces microautophagy and chaperone-mediated autophagy (Klionsky, 2007) that we will briefly describe here. The last stage of autophagy is the fusion of the amphisomes with lysosomes to degrade their autophagic cargoes and to recycle nutrients (to meet the metabolic demand) and membranes (to permit ongoing lysosomal function).
The omegasome serves as a PAS to accommodate the two ubiquitin-like conjugation systems (Atg12-Atg5, Atg16 and LC3-II, the phosphatidylethanolamine containing LC3, the mammalian ortholog of the yeast Atg8) that act sequentially to elongate the phagophore membrane and thus form the autophagosome (Nakatogawa et al., 2009). Transfer of material from the autophagosome to the lysosomal compartment following a kiss-and-run fusion process in which two separate vesicles are maintained.
Kroemer and coworkers have shown that the IP3R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed between the IP3R and Beclin 1, an interaction that is regulated by Bcl-2 (Vicencio et al., 2009). The cleavage of Atg proteins by caspases and calpains has been proposed as a possible additional mechanism modulating autophagy. Recently another member of the FoxO protein family, FoxO1, has been shown to regulate the expression of key autophagy genes, Pik3c3, Atg12, and Gabarapl1 in hepatocytes in an insulin-dependent manner (Liu et al., 2009). The complexity of the autophagic response to p53 is further increased by the ability of cytoplasmic p53 to limit autophagy (Tasdemir et al., 2008). The fact that autophagy and lysosomal formation are both coordinated by TFEB offers a possible therapeutic target that could be used to boost the autophagic pathway when appropriate. In the heart, basal autophagy is necessary to maintain cellular homeostasis and is upregulated in response to stress in hypertensive heart disease, heart failure, cardiac hypertrophy, and ischemia-reperfusion (Nakai et al., 2007). As women have two X chromosomes, it is more likely there is a dominant normal blood-clotting gene in the other X chromosome, therefore inhibiting the recessive gene from activating.
In contrast to macroautophagy, which starts with the formation of a vacuole, known as the autophagosome, that sequesters cytoplasmic components, microautophagy consists of the direct uptake of fractions of the cytoplasm by the lysosomal membrane.
Whereas the mobility of autophagic vacuoles is dependent on microtubules, fusion events between autophagic vacuoles and lysosomes seem to be independent of cytoskeletal elements. The phosphorylation of Beclin 1 by Death-associated protein kinase (DAPK) also triggers the dissociation of Bcl-2 from Beclin 1. More recently it has been suggested that the mitochondrial outer membrane may be another source of the isolation membrane (Hailey et al., 2010).
It is impossible to rule out the possibility that these proteins could be involved in the closing of autophagosomes (reviewed in Rusten and Stenmark, 2009).
However, fusion with lysosomes can be microtubule-independent during starvation-induced autophagy when autophagosomes are formed in the vicinity of lysosomes (Fass et al., 2006). Interestingly, Neufeld and coworkers showed that p70S6K is up-regulated during starvation-induced autophagy in the Drosophila fat body (Scott et al., 2004). In this setting, the activation of AMPK and stimulation of autophagy are dependent on CaMKK-b.
The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in the dissociation of the Beclin 1:Bcl-2 complex will be discussed in the next section. The IP3R is known to be located in the membranes of the ER as well as in ER-mitochondrial contact sites, and IP3R blockade triggers the autophagy of both ER and mitochondria, as observed in starvation-induced autophagy. Interestingly, the truncated form of Atg5 generated by calpain 1 cleavage is translocated into the mitochondria and induces apoptosis (Yousefi et al., 2006). Defective autophagy is observed in many human diseases, and its stimulation is beneficial in most cases. In the case of hemophilia, when women are given the trait they most likely become carriers of the trait, but when men inherit the trait, they mostly inherit the disease. A long-standing question regarding autophagy was to identify the origin of the phagophore and to decipher the molecular basis of the biogenesis of autophagosomes. Not shown in the Figure, BH3-containing proteins can dissociate the Beclin 1:Bcl-2 interaction by competing with the Beclin 1 BH3 domain independently of the modification of the phosphorylation status of the proteins in the complex. According to this scenario, the mitochondria-ER contact site provides the growing phagophore with lipids. A major unanswered question about the stimulation of autophagy during starvation is how amino acids signal to mTOR (Meijer and Dubbelhuis, 2004).
Mammalian cells probably have a regulatory feedback pathway involving S6K that regulates autophagy (Klionsky et al., 2005). Overall these findings point to the central role of Beclin1:hVps34 complexes in the cross-talk between autophagy and apoptosis.
ER stressors, such as tunicamycin and thapsigargin, also induce autophagy of the ER and, to a lesser extent, of mitochondria. Autophagy plays a more complex role in cancer, because it can be a tumor suppressor mechanism, but can also become a cytoprotective mechanism in tumors, where it contributes to cell survival in a context of metabolic stress and in response to cancer treatments. This is different from Mendelian genetics, because in sex-linked genetics, men are more likely to have the traits displayed in their genotypes instead of having an equal chance with the female of having the traits displayed. The discovery of ATG genes in yeast was a major milestone in our understanding of autophagy (Nakatogawa et al., 2009). The plasma membrane, through Atg16L1 decorated vesicles derived from coated pits, is also a source of membrane for the phagophore (Ravikumar et al., 2010a).
Interestingly, a recent study reports that the anti-apoptotic protein FLIP, which blocks the activation of caspase 8 downstream of death receptors, is also an anti-autophagy molecule by blocking the formation of LC3-II via its interaction with Atg3 (Lee et al., 2009) (Figure 2). More than 15 Atg proteins, plus class III PI3K or hVps34, are required to construct the autophagosome. Thus it appears that hVps34 acts both as a down-regulator of autophagy (acting as an amino acid sensor) and as an up-regulator (because it is a component of Beclin 1 complexes) of autophagy. This loop could provide a way to regulate the activity of mTORC1 during starvation-induced autophagy.
Another potential candidate of autophagy regulation downstream of AMPK is the Elongation factor-2 kinase (eEF-2 kinase) that controls the rate of peptide elongation (Hait et al., 2006). Microautophagy is dependent on GTP hydrolysis and on calcium (Uttenweiler and Mayer, 2008).
Whatever the origin of the membrane, Atg proteins are retrieved from the autophagosome membrane after closure, with the exception of a fraction of LC3-II, which is transported into the lysosomal compartment (Yang and Klionsky, 2010). Activation of eEF-2 kinase increases autophagy while slowing down protein translation (Wu et al., 2006).
Autophagy promoted by IP3R inhibition cannot be attributed to a modulation of steady-state Ca2+ levels in the ER or in the cytosol (Vicencio et al., 2009). The formation of the autophagosome is a multistep process that includes the biogenesis of the isolation membrane, followed by its elongation and closure.
The expansion and closure of the autophagosomal membrane are dependent on the Atg12 and LC3 conjugation systems. Following on from this discovery, several methods based on the analysis of the LC3 protein have been developed to monitor autophagy (Mizushima et al., 2010). Moreover, the rate-limiting factor that enables essential amino acids to inhibit mTORC1 has been identified as L-glutamine (Nicklin et al., 2009).
The process also requires the shuttling of Atg9, the only transmembrane Atg, between a peripheral site and the isolation membrane (Nakatogawa et al., 2009) (Figure 2). The Atg12-Atg5 conjugate associated with Atg16 contributes to the stimulation of the conjugation of LC3-I to phosphatidylethanolamine (PE) to generate LC3-II. During periods of ATP depletion, AMPK is activated and eEF-2 kinase is phosphorylated (Browne et al., 2004) making a balance between inhibition of peptide elongation and induction of autophagy. Chaperone-mediated autophagy (CMA) is a selective form of autophagy that has so far only been described in mammalian cells (Cuervo, 2009). Expansion of the autophagosomal membrane is probably dependent on the supply of lipids by Atg9 that cycles between a peripheral pool and the growing isolation membrane or phagophore.
How eEF-2 kinase impinges on the molecular machinery of autophagy remains to be investigated. This motif is recognized by the cytosolic constitutive chaperone hsc70 (heat shock cognate of the Hsp70 family).
In this Figure, protein kinases with substrates in the autophagic machinery are boxed in rectangles. But the cytoplasmic form of p53 has been shown to have an inhibitory effect on autophagy (Tasdemir et al., 2008). The lysosomal membrane protein, LAMP-2A, serves as a receptor in the translocation of unfolded polypeptides across the lysosomal membrane. KFERQ-like motifs are found mainly in cytosolic proteins, and it is estimated that about 30% of cytosolic proteins contain this motif.
CMA performs several general functions, such as the elimination of oxidazed proteins and the removal of misfolded proteins, and also provides amino acids during prolonged periods of starvation. Prevention of the age-related decline of CMA is beneficial for the homeostasis of organs and function (Zhang and Cuervo, 2008). This observation is indicative of the potential importance of CMA and macroautophagy, as we discuss below, as possible anti-aging mechanisms.
CMA is also involved in more specific functions, such as antigen presentation by MHC class II molecules, neurone survival, and kidney growth (Cuervo, 2009).




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