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Death review

As part of the 40th anniversary edition of Cell Doug Green and Beth Levine provide a succinct overview of the role(s) and regulation of autophagy and different cell death pathways in cell fate.

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Ferrostatin update

Here is our most recent paper showing that ferrostatin-1 (Fer-1) and analogs can prevent cell death in various disease models and further elucidating the mechanism of Fer-1 action.  A great team effort!

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Sphere screen

There is a lot of interest in using multicellular tumor spheres (MCSs) in screens, as opposed to cells cultured on 2D substrates, to find new lethal small molecules that may be more likely to be active against tumors in vivo.  This interesting paper identifies a new compound, VLX600, that is selectively lethal to the central 'core' area of MCSs formed from HCT116 cells.  It appears to disrupts mitochondrial metabolism, but the target remains unclear.  

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Necroptosis in ALS

A new report suggests that the death of motor neurons in ALS (Lou Gehrig's disease) involves activation of the necroptotic pathway.  Yet more evidence that we should be looking beyond apoptotic pathways when it comes to disease pathogenesis and treatment.

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SOD switch

The superoxide dismutases (SODs) defend the cell against superoxide accumulation.  The Germain Lab now has an interesting paper showing that in breast cancer the there is a switch from predominant SOD2 to predominant SOD1 expression.  If you then inhibit SOD1 using the small molecule LCS-1 developed in the Varmus lab you can kill these cells effectively.

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New Routes to Tumor Formation

This useful summary of two recent papers describes how certain brain cancer can apparently arise from mechanisms other than gene mutation - in these cases, evidently epigenetic alterations.  So...what triggers those alterations?

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Drug target ID using an ultra complex shRNA library

Defining drug targets is not easy.  In this paper groups from Stanford and UCSF use ultra-complex shRNA libraries to quickly determine that the target of the novel lethal small molecule STF-118804 was NAMPT, an enzyme needed for NAD+ synthesis.  This approach could be applied in some cases (like the yeast HIP assay) to quickly define candidate drug targets.

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Journal club: Mitoflashes & aging

A new report suggests that the frequency of 'mitoflashes' on the pharynx of C. elegans in early adulthood is a good predictor of lifespan.  Fewer flashes = longer lifespan.  Unclear exactly what people think a mitoflash might be (ROS? H+?), but a very interesting predictor nonetheless.  Will also be interesting to see how mitoflashes might relate to the activation of the mitochondrial UPR, which recently has also been linked to aging.

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Preprint server for biology

The physics preprint server arXiv.org has been around awhile and, as I understand, is very popular within that community for the rapid communication of results.  CSHL has now started one for biology.  Will it catch on? 

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Journal Club: Autosis

Beth Levine's lab reports a new form of cell death - autosis - that can be induced by a cell-penetrating, autophagy-inducing peptide tat-Beclin-1.  They then use a small molecule screen to identify chemical suppressors of this particular cell death phenotype and find Na+/K+-channel blockers are effective inhibitors of this type of death.

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Journal Club: Targets of 4-HNE

4-hydroxynonenal (4-HNE) is a toxic breakdown product of damaged fatty acids that is thought to contribute to cell death.  Ben Cravatt's lab has now used a variation of their previously reported cysteine-reactivity profiling assay to identify novel targets of 4-HNE reactivity, including the kinase ZAK.  Interestingly, the 'HNE-ylation' of ZAK impacts the response of cancer cells to oxidative stress.  They don't talk about it in the paper, but interestingly two other prominent targets of HNE modification are involved in 1-carbon metabolism, including the oncogene PHGDH.  Could be an interesting link here.

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Journal Club: TBI, ROS & Glutathione

A new paper uses intravital imaging to show that traumatic brain injury (TBI) results in ROS-dependent brain cell death.  Cell death is totally prevented by the provisioning of glutathione [which amazingly can penetrate across the skull bone], consistent with the ROS being essential for cell death.  The ROS source and ROS targets that mediate lethality remain unclear, but nonetheless suggest exciting parallels to the ferroptotic process we described recently.

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Congrats to the Stockwell Lab!

Congratulations to all my former colleagues in the Stockwell lab on their paper in Cell.  This work describes how the small molecule RSL3 (more specifically 1S,3R-RSL3) binds to and inactivates the glutathione peroxidase GPX4.  This results in enhanced levels of lipid ROS and ferroptotic cell death in various cancer cells.  

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Journal club: Pyroptosis in HIV-infected T cells

A new report suggests that most CD4+ T cells infected with the HIV virus die via caspase-1-mediated pyroptosis, not caspase-3-mediated apoptosis.  Pyroptosis is a pro-inflammatory mode of cell death, possibly explaining the connection between HIV infection and persistent inflammation.

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Single cell regulation of cell death by autophagy

A major controversy in the cell death field concerns the role of autophagy: in some contexts it appears to protect from cell death, in others to promote (or even execute) death.  A new report from the Thornburn lab suggests that stochastic fluctuation in the activity of the autophagy pathway have an important impact on cell fate in response to different lethal stimuli and may help account for some of the controversy in the literature.

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Genome-wide CRISPR/Cas screens

Ever since the first reports earlier this year of using the CRISPR/Cas system to modify individual gene function in human cells it has been inevitable that we would see whole-genome modification screens.  The first two such reports are out today in Science and look very interesting.  Genome-wide combination (e.g. synthetic lethal) screens cannot be far behind.  Does this signal the end of genome-wide RNAi screening?

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