Abstract
Anastasis (Greek for "rising to life") is a cell recovery phenomenon that rescues dying cells from the brink of cell death. We recently discovered anastasis to occur after the execution-stage of apoptosis in vitro and in vivo. Promoting anastasis could in principle preserve injured cells that are difficult to replace, such as cardiomyocytes and neurons. Conversely, arresting anastasis in dying cancer cells after cancer therapies could improve treatment efficacy. To develop new therapies that promote or inhibit anastasis, it is essential to identify the key regulators and mediators of anastasis - the therapeutic targets. Therefore, we performed time-course microarray analysis to explore the molecular mechanisms of anastasis during reversal of ethanol-induced apoptosis in mouse primary liver cells. We found striking changes in transcription of genes involved in multiple pathways, including early activation of pro-cell survival, anti-oxidation, cell cycle arrest, histone modification, DNA-damage and stress-inducible responses, and at delayed times, angiogenesis and cell migration. Validation with RT-PCR confirmed similar changes in the human liver cancer cell line, HepG2, during anastasis. Here, we present the time-course whole-genome gene expression dataset revealing gene expression profiles during the reversal of apoptosis. This dataset provides important insights into the physiological, pathological, and therapeutic implications of anastasis.
Highlights
Apoptosis (Greek for “falling to death”) is essential for normal development and homeostasis of multicellular organisms by eliminating unwanted, injured, or dangerous cells[1,2,3]
Intrinsic and extrinsic pro-apoptotic signals can converge at mitochondria, leading to mitochondrial outer membrane permeabilization (MOMP), which releases cell execution factors, such as cytochrome c to trigger activation of apoptotic proteases including caspase-3 and -710,11, small mitochondria-derived activator of caspases (Smac)/direct IAP binding protein with low pI (DIABLO) to eliminate inhibitor of apoptosis protein (IAP) which suppresses caspase activation[12,13], and apoptosis-inducing factor (AIF) and endonuclease G to destroy DNA14–17
To detect reversal of apoptosis in live animals, we have further developed a new in vivo caspase biosensor, designated “CaspaseTracker”[33], to identify and track somatic, germ and stem cells that recover after transient cell death inductions, and potentially during normal development and homeostasis in Drosophila melanogaster after caspase activation[33,34], the hallmark of apoptosis[4,35]
Summary
Any reports and responses or comments on the article can be found at the end of the article. Keywords Anastasis, apoptosis, Cell Death, Cell Survival, Gene Expression, Recovery, Repair, Reversal of Apoptosis. We have added new data that support our conclusions. Our RT-PCR reveals that a human liver cancer cell line displays similar gene expression profile during anastasis as observed in mouse primary liver cells. Additional microarray statistical analysis is included as supplementary data. We have discussed the potential molecular mechanisms, physiological and pathological consequences, and therapeutic potentials of anastasis
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