Autophagy and Caspases: A New Cell Death Program

Every cell in our body contains a “self-destruction” program. This cell death is a critical process allowing replacement of damaged cells with healthy ones to prevent wide range of diseases. When the cell’s death mechanism gets “stuck” and is not activated, cancer can result. In healthy cells there is a balanced system of proteins, some of which activate the normal death mechanism, and some of which inhibit this process. This is like the system of gas and brakes in a car. Researchers have found that cancer cells lack a protein, called ARTS, which is crucial for activating the cells’ death mechanism. The lack of ARTS causes cancer cells to escape death and become “immortal.” Small ARTS-like molecules have been discovered that can penetrate cancerous cells and reactivate the cell death program, effectively making the cancer cells “commit suicide.” We envision that these ARTS-like molecules will provide novel therapy for cancer.

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Induction of Hypersensitive Cell Death by a Fungal Protein in Cultures of Tobacco Cells

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi.1998.11.2.115 ◽

1998 ◽

Vol 11 (2) ◽

pp. 115-123 ◽

Cited By ~ 59

Author(s):

Akira Yano ◽

Kaoru Suzuki ◽

Hirofumi Uchimiya ◽

Hideaki Shinshi

Keyword(s):

Cell Death ◽

Specific Interaction ◽

Trichoderma Viride ◽

Defense Responses ◽

Hypersensitive Reaction ◽

Hypersensitive Cell Death ◽

Tobacco Cells ◽

Bright Yellow ◽

Cell Death Program ◽

Cellular Signal

Treatment of suspension-cultured tobacco (Nicotiana tabacum cv. Xanthi) cells (line XD6S) with fungal proteinaceous elicitors, namely, xylanase (EC 3.2.1.8) from Trichoderma viride (TvX) and xylanase from T. reesei (TrX), induced shrinkage of the cytoplasm, condensation of the nucleus, and, finally, cell death, which were accompanied by typical defense responses that included an oxidative burst and expression of defense genes. A Ca2+ channel blocker, Gd3+, inhibited the typical response of XD6S cells to TvX, which resembled the hypersensitive reaction (HR). These results suggested that the influx of Ca2+ ions plays an important role as a secondary signal. The HR was not observed in TvX-treated tobacco cells (line BY-2) derived from cv. Bright Yellow 2. This result suggests that key features of cultivar-specific interaction can be observed in cultures of tobacco cells. Xylanase from Bacillus circulans (BcX) and B. subtilis (BsX), which has enzymatic properties similar to those of TvX but an amino acid sequence different from that of TvX, did not induce the HR-like response in XD6S cells. These results suggest that the elicitor action of TvX is not due to its ability to hydrolyze cell walls but requires the TvX-specific recognition factors in plant cells. Thus, TvX-induced cell death was not due to some general toxic effect, but seems to be mediated by the activation of a specific cellular signal-transduction cascade that converges with a pathway that activates the intracellular cell death program.

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PolyQ disease: misfiring of a developmental cell death program?

Trends in Cell Biology ◽

10.1016/j.tcb.2012.11.003 ◽

2013 ◽

Vol 23 (4) ◽

pp. 168-174 ◽

Cited By ~ 39

Author(s):

Elyse S. Blum ◽

Andrew R. Schwendeman ◽

Shai Shaham

Keyword(s):

Cell Death ◽

Polyq Disease ◽

Cell Death Program ◽

Developmental Cell Death

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GmNAC81 Inversely Modulates Leaf Senescence and Drought Tolerance

Frontiers in Genetics ◽

10.3389/fgene.2020.601876 ◽

2020 ◽

Vol 11 ◽

Author(s):

Dalton O. Ferreira ◽

Otto T. Fraga ◽

Maiana R. Pimenta ◽

Hanna D. N. Caetano ◽

João Paulo B. Machado ◽

...

Keyword(s):

Cell Death ◽

Drought Tolerance ◽

Leaf Senescence ◽

Control Line ◽

Aba Signaling ◽

Downstream Effector ◽

Relative Water ◽

Cell Death Program ◽

Transgenic Lines ◽

Increased Sensitivity

Glycine max NAC81 (GmNAC81) is a downstream effector of the DCD/NRP-mediated cell death signaling, which interacts with GmNAC30 to fully induce the caspase 1-like vacuolar processing enzyme (VPE) expression, the executioner of the cell death program. GmNAC81 has been previously shown to positively modulate leaf senescence via the NRP/GmNAC81/VPE signaling module. Here, we examined the transcriptome induced by GmNAC81 overexpression and leaf senescence and showed that GmNAC81 further modulates leaf senescence by regulating an extensive repertoire of functionally characterized senescence-associated genes (SAGs). Because the NRP/GmNAC81/VPE signaling circuit also relays stress-induced cell death signals, we examined the effect of GmNAC81 overexpression in drought responses. Enhanced GmNAC81 expression in the transgenic lines increased sensitivity to water deprivation. Under progressive drought, the GmNAC81-overexpressing lines displayed severe leaf wilting, a larger and faster decline in leaf Ψw, relative water content (RWC), photosynthesis rate, stomatal conductance, and transpiration rate, in addition to higher Ci/Ca and lower Fm/Fv ratios compared to the BR16 control line. Collectively, these results indicate that the photosynthetic activity and apparatus were more affected by drought in the transgenic lines. Consistent with hypersensitivity to drought, chlorophyll loss, and lipid peroxidation were higher in the GmNAC81-overexpressing lines than in BR16 under dehydration. In addition to inducing VPE expression, GmNAC81 overexpression uncovered the regulation of typical drought-responsive genes. In particular, key regulators and effectors of ABA signaling were suppressed by GmNAC81 overexpression. These results suggest that GmNAC81 may negatively control drought tolerance not only via VPE activation but also via suppression of ABA signaling.

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Future Therapeutic Directions for Smac-Mimetics

Cells ◽

10.3390/cells9020406 ◽

2020 ◽

Vol 9 (2) ◽

pp. 406 ◽

Cited By ~ 10

Author(s):

Emma Morrish ◽

Gabriela Brumatti ◽

John Silke

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Tumor Growth ◽

Cancer Cells ◽

Inhibitor Of Apoptosis ◽

Growth Strategies ◽

Promote Tumor Growth ◽

Cell Death Program ◽

Smac Mimetics ◽

Promote Cell Death

It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy.

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The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

Oncogene ◽

10.1038/sj.onc.1203681 ◽

2000 ◽

Vol 19 (41) ◽

pp. 4669-4684 ◽

Cited By ~ 78

Author(s):

Katherine Elliott ◽

Kai Ge ◽

Wei Du ◽

George C Prendergast

Keyword(s):

Cell Death ◽

Adaptor Protein ◽

Cell Death Program

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