p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Lin, Lih-Yuan; Ye, Y; Zakeri, Zahra

doi:10.1038/sj.cdd.4401717

Cited by 23 publications

(30 citation statements)

References 71 publications

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“…Western blot analysis was performed as described by Lin et al (2006). Briefly, treated cells were scraped and washed with ice-cold 1 × PBS before whole cell lysate proteins were collected in RIPA buffer and quantified using the BioRad protein assay and an Ultrospec III spectrophotometer (Pharmacia LKB, Sweden).…”

Section: Methodsmentioning

confidence: 99%

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mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection

et al. 2014

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Autophagy, a stress response activated in influenza A virus infection helps the cell avoid apoptosis. However, in the absence of apoptosis infected cells undergo vastly expanded autophagy and nevertheless die in the presence of necrostatin but not of autophagy inhibitors. Combinations of inhibitors indicate that the controls of protective and lethal autophagy are different. Infection that triggers apoptosis also triggers canonical autophagy signaling exhibiting transient PI3K and mTORC1 activity. In terminal autophagy phospho-mTOR(Ser2448) is suppressed while mTORC1, PI3K and mTORC2 activities increase. mTORC1 substrate p70S6K becomes highly phosphorylated while its activity, now regulated by mTORC2, is required for LC3-II formation. Inhibition of mTORC2/p70S6K, unlike that of PI3K/mTORC1, blocks expanded autophagy in the absence of apoptosis but not moderate autophagy. Inhibitors of expanded autophagy limit virus reproduction. Thus expanded, lethal autophagy is activated by a signaling mechanism different from autophagy that helps cells survive toxic or stressful episodes.

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Section: Methodsmentioning

confidence: 99%

“…Cytochemical analysis was performed as described by Lin et al (2006). Cells were seeded on flame-sterilized glass cover slips, allowed to attach overnight, infected and treated as above.…”

Section: Methodsmentioning

confidence: 99%

mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection

et al. 2014

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“…Additionally inducing cell death in the day 10.5 embryo with cyclophosphamide (CP), which leads to 90% cell death, we isolated using both yeast two hybrid and pulldown assay a cyclin like interacting protein (p35) that appears to be cleaved by a calpain during cell death to p25 and to interact and activate CDK5 only during cell death (Zhu et al, 2002). Interestingly the activation of CDK5 does not require caspase, functional mitochondria-related bin, or p53 (Lin et al, 2006;Ye et al, in preparation). We can conclude that the activity of CDK5 during diVerentiation is regulated by a larger interacting activating protein p35; and during activation of cell death activated calpains cleave the p35 to p25, which interacts and activates CDK5 which then acts to propagate cell death.…”

Section: Cell Death Sets Up the Correct Patterning Of The Embryo And mentioning

confidence: 99%

Cell death in development: shaping the embryo

Penaloza

Lin

Lockshin

et al. 2006

Histochem Cell Biol

111

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Cell death in animals is normally classified as type I (apoptotic), type II (autophagic) or necrotic. Of the biologically controlled types of death, in most embryos apoptosis is the most common, although in metamorphosis and in cells with massive cytoplasm type II is often seen, and intermediate forms are seen. For vertebrate embryos other than mammals, apoptosis is not seen prior to gastrulation but thereafter is used to sculpt the organs of the embryo, while overproduction of cells with subsequent death of excess cells is a common means of generating high specificity with low information cost. In zebrafish at least, the inability of embryos prior to the maternal-zygotic transition to undergo apoptosis appears to derive from the inability of the cells to resist lysis once apoptosis begins, rather than any inhibition of apoptosis. In mammalian embryos, apoptosis is seen during cavitation. Thereafter, as in other embryos, cell death plays a major role in shaping and sculpting the embryo. In those situations that have been carefully studied, cell death is under tight genetic control (including regulation of gene products whose function in cell death is not yet known, such as cdk5), with activation of apoptosis sometimes regulated by local environmental variables.

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“…We have previously shown a direct correlation between trypan blue exclusion and other viability assays (18). Live (white) and dead (blue) cells, were counted on a hemocytometer, with cell viability expressed as percent dead cells above mock.…”

Section: Methodsmentioning

confidence: 99%

Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication

McLean

Wudzinska

Datan

et al. 2011

Journal of Biological Chemistry

232

223

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Over 2.5 billion people live in areas at high risk for Dengue and related flavivirus infections (1). Dengue hemorrhagic fever, a severe complication present in ϳ5% of cases, claims more lives annually than all other hemorrhagic fevers combined (2); much of the damage is caused by death of infected cells. The fate of infected cells depends on cell type. Although flavivirus induces apoptosis of neurons and macrophages, infected hepatocytes and epithelial cells do not die. We find that flavivirus up-regulates autophagy in MDCK 3 renal epithelial cells and other cell types and subsequently protects them. We further identify nonstructural protein NS4A of both Dengue-2 and Modoc viruses as the sole viral mediator of autophagy up-regulation and protection against death. Up-regulation of autophagosomes by either live virus infection or NS4A expression depends on PI3K and is important for replication of flavivirus in renal epithelial cells. Flaviviruses often persist in liver and kidney following the acute phase of infection, suggesting that infected cells evade destruction by the host immune response, likely by flavivirusinduced up-regulation of autophagy in these cells. In vitro infection of hepatocytes and fibroblasts leads to up-regulation in autophagy and protection against death (3, 4). More relevant, Dengue-2 viruses replicate within the hepatocyte autophagosomes (5), and inhibition of autophagy attenuates virus replication (3). We extend these findings by identifying the nonstructural viral protein NS4A as the virus-encoded protein that up-regulates autophagy and thus protects the host cell against death, providing a well protected host cell for long term replication of virus.The flavivirus genome contains 10 genes encoding an ϳ11-kDa polyprotein precursor that binds to the ER membrane after translation at the rough ER as follows: three structural proteins (capsid (core) protein, pre-membrane protein ,and envelope glycoprotein) and seven nonstructural genes (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) that mediate viral replication, assembly, and evasion of the host immune system. The active proteins are cleaved from the ER-bound viral polyprotein by cellular proteases signalase and furin and viral protease NS3/ 2B. NS3 is both a viral protease (with required cofactor NS2B (6)) and a viral ATP-dependent helicase (7, 8); NS5 is an RNAdependent RNA polymerase and methyltransferase (9) responsible for virus genome replication, whereas NS1 is possibly a part of the viral replication complex (10). The small hydrophobic flavivirus proteins (NS2A, NS4A, and NS4B) remain the most poorly characterized. NS2A is required for the assembly of new flavivirus virions; NS4A associates with the virus replication complex and induces ER membrane rearrangements (discussed below), and NS4B is an antagonist of interferon. Flavivirus NS4A is an ϳ16-kDa membrane-associated protein consisting of four transmembrane helices and an N-terminal cytosolic region. Once the viral genome is translated in the ER,

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p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Cited by 23 publications

References 71 publications

mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection

mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection

Cell death in development: shaping the embryo

Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication

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