Abstract
Apoptosis is a type of programmed cell death that is essential for normal organismal development and homeostasis of multicellular organisms by eliminating unwanted, injured, or dangerous cells. This cell suicide process is generally assumed to be irreversible. However, accumulating studies suggest that dying cells can recover from the brink of cell death. We recently discovered an unexpected reversibility of the execution-stage of apoptosis in vitro and in vivo, and proposed the term anastasis (Greek for "rising to life") to describe this cell recovery phenomenon. 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-survival genes, cell cycle arrest, stress-inducible responses, and at delayed times, cell migration and angiogenesis. 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”) was generally assumed to be an irreversible cell suicide process because it involves rapid and massive cell destruction[1,2,3,4,5,6,7]
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 -78,9, small mitochondria-derived activator of caspases (Smac)/direct IAP binding protein with low pI (DIABLO) to eliminate inhibitor of apoptosis protein (IAP) inhibition of caspase activation[10,11], and apoptosis-inducing factor (AIF) and endonuclease G to destroy DNA12–15
We have further demonstrated that dying cells can reverse apoptosis even after reaching the generally assumed “point of no return”, such as MOMP-mediated cytochrome c release, caspase activation, DNA damage, nuclear fragmentation, and apoptotic body formation[26,27,28]
Summary
Apoptosis (Greek for “falling to death”) was generally assumed to be an irreversible cell suicide process because it involves rapid and massive cell destruction[1,2,3,4,5,6,7]. To detect reversal of apoptosis in live animals, we have further developed a new in vivo caspase biosensor, designated “CaspaseTracker”[30], and successfully identified and tracked somatic, germ and stem cells to survive transiently-induced cell death, and potentially during normal development and homeostasis in Drosophila melanogaster after caspase activation[30,31], the hallmark of apoptosis[2,32]. We refer to this recovery phenomenon as “anastasis”[27], which means “rising to life” in Greek, for the reversal of apoptosis. We present our time-course microarray data, which reveals the molecular signature of anastasis
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