Disease relevance of ATG5

• The clustering and marked concentration of these molecules in the surface blebs of apoptotic cells, and their modification by apoptosis-specific proteolytic cleavage and/or phosphorylation at these sites, has focused attention on a unique apoptotic setting as the potential initiating stimulus for systemic autoimmunity [1].
• Hypertrophic scar cells fail to undergo a form of apoptosis specific to contractile collagen-the role of tissue transglutaminase [2].
• This study involved an immunohistochemical "profiling" of prostate tissue specimens from patients who underwent prostatectomy for localized prostate cancer, to identify apoptosis-specific alterations associated with premalignant precursor lesions [3].
• Similar apoptosis-specific beta-catenin cleavage was also demonstrated in the rat hepatoma cell line McA-RH7777, suggesting that the beta-catenin cleavage is a common event in apoptosis in various cell types [4].
• Elevated serum levels of epithelial cell apoptosis-specific cytokeratin 18 neoepitope m30 in critically ill patients [5].

High impact information on ATG5

• As the p53-dependent apoptosis pathway is not well understood, we sought to identify apoptosis-specific p53 target genes using a subtractive cloning strategy [6].
• Recent studies examining cells lacking the autophagy genes Atg5 and Atg7 have demonstrated that autophagy plays essential roles in cell survival during starvation, in innate cell clearance of microbial pathogens, and in neural cell maintenance [7].
• In the periphery, Atg5(-/-) CD8(+) T lymphocytes displayed dramatically increased cell death [7].
• A critical role for the autophagy gene Atg5 in T cell survival and proliferation [7].
• However, the numbers of total thymocytes and peripheral T and B lymphocytes were reduced in Atg5 chimeras [7].

Chemical compound and disease context of ATG5

• Two-dimensional gel analysis of apoptosis-specific p53 isoforms induced by 2-methoxyestradiol in human lung cancer cells [8].

Biological context of ATG5

• The ubiquitin-like conjugation reactions, ATG8/microtubule-associated protein 1 light chain 3/MAP1LC3 (LC3) to phosphatidylethanolamine (PE) and ATG12 to ATG5, are biochemical hallmarks for autophagy, a cellular process that degrades bulk cellular proteins and organelles [9].
• Cells harboring the accumulated vacuoles triggered by IFN-gamma or Atg5 expression become dead, and vacuole formation precedes cell death [10].
• Down-regulation of Atg5 expression in HeLa cells suppresses cell death and vacuole formation induced by IFN-gamma [10].
• Increased apoptosis was demonstrable among SLE sera-cultured cells by ELISA for apoptosis-specific DNA fragments and terminal deoxynucleotidyl transferase (TdT) in situ death analysis [11].
• Assignment of the yeast APG5 human homologue APG5L to chromosome band 6q21 by fluorescence in situ hybridisation [12].

Anatomical context of ATG5

• Furthermore, a potent stimulating activity for ATG12-ATG5 conjugation was detected in mammalian cell extracts, and was surprisingly identified as ribosomes [9].
• Furthermore, Atg5(-/-) CD4(+) and CD8(+) T cells failed to undergo efficient proliferation after TCR stimulation [7].
• Truncated Atg5 translocated from the cytosol to mitochondria, associated with the anti-apoptotic molecule Bcl-x(L) and triggered cytochrome c release and caspase activation [13].
• Furthermore, the induced phosphatase activity coimmunoprecipitated with the hyperphosphorylated RB and was active in a cell-free system that reproduced the growth arrest- and apoptosis-specific RB dephosphorylation, which was inhibitable by calyculin A but not zinc [14].
• The viability of the T cells cocultured with the HIV-1-infected macrophage cell lines or the primary monocytes as determined by propidium iodide staining was unaltered and there was no increase in apoptosis-specific DNA strand breaks or increased expression of Bcl-2 in the T cells [15].

Associations of ATG5 with chemical compounds

• This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-x(L)), and was also modulated by Bcl-x(L) [16].
• Data were confirmed by apoptosis-specific fluorescence-activated cell sorter analysis of confluent HUVEC cultures, which displayed after long-term exposure to 30 mmol/l glucose a 1.5-fold higher prevalence of apoptosis than control cultures exposed to 5 mmol/l glucose (P < 0.005) [17].
• Treatment of tumour cells with hyperforin resulted in a dose-dependent generation of apoptotic oligonucleosomes, typical DNA-laddering and apoptosis-specific morphological changes [18].
• Several hallmarks of apoptosis, including DNA laddering, chromatin condensation and fragmentation, and an apoptosis specific cleavage of 28S and 18S ribosomal RNA were observed after treatment with curcumin [19].
• Bisbenzimide staining of the fixed cells revealed typical apoptotic structures (apoptotic bodies), and the apoptosis-specific "DNA ladder pattern" resulting from internucleosomal cleavage was identified by gel electrophoresis [20].

Regulatory relationships of ATG5

• Furthermore, Atg5 deficiency as well as the eIF2alpha A/A mutation increased the number of cells showing polyQ72 aggregates and polyQ72-induced caspase-12 activation [21].
• The serine protease inhibitor TPCK (N-tosyl-L-phenylalanyl chloromethyl ketone) specifically inhibited apoptosis-specific DNA fragmentation induced by buprenorphine hydrochloride; however, cell viability measurements revealed that cell death still occurred in NG108-15 cells [22].
• Gene expression profiles were examined for both GP5-expressing cells and bystanders by apoptosis-specific macroarrays and gene chip-based microarrays, but no genes related to apoptosis were specifically regulated [23].

Other interactions of ATG5

• Here, we show that Atg5, which is known to function in autophagy, contributes to autophagic cell death by interacting with Fas-associated protein with death domain (FADD) [10].
• In cells, ATG12-ATG5 conjugation appears to be required for LC3-PE conjugation [9].
• Enhancement of autophagy by ATG5 protected against Bnip3-mediated cell death, whereas inhibition of autophagy by ATG5K130R enhanced cell death [24].
• We further show that two hydrophobic residues within the ubiquitin-fold region are important for autophagy: mutation at Y149 affects conjugate formation catalyzed by Atg10, an E2-like enzyme, while mutation at F154 has no effect on Atg12-Atg5 conjugate formation but its hydrophobic nature is essential for autophagy [25].
• Cleavage of SATB1 was mediated by caspase-3 and was apoptosis specific [26].

Analytical, diagnostic and therapeutic context of ATG5

• Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death [10].
• Expression, purification and crystallization of the Atg5-Atg16 complex essential for autophagy [27].
• In contrast, silencing the Atg5 gene with short interfering RNA (siRNA) resulted in partial resistance to chemotherapy [13].
• Two complementary techniques were used to detect apoptosis-specific internucleosomal DNA fragmentation: agarose gel electrophoresis and in situ labeling of apoptotic cells by terminal dUTP nick end labeling [28].
• Fibroblast apoptosis was determined by cell morphology, apoptosis-specific protein expression, and DNA fragmentation by TdT-mediated dUTP nick-end labeling (TUNEL) [29].

References