Abstract
Mitotic catastrophe (MC) has long been accounted as a cell death path activated by premature or inappropriate entry of cells into mitosis following chemical or physical stresses. Although various possible explanations related to MC have been formulated, no general accepted definition of this phenomenon has been found yet. Recent evidences, however, demonstrate that MC is not a distinguished way of cell death, rather a “prestage” anticipating cell death, taking place in mitotically disrupted cells, which later occurs via necrosis or apoptosis. Moreover, even though it is widely accepted that MC is the main outcome after ionizing radiation treatment or treatment with drugs that influence microtubule assembly/stability inducing mitotic failure, the final cell death pathway and the final outcome of MC, which strongly depend on the cell type and its related molecular profile, still need to be fully elucidated. Post-mitotic cells, like neurons in the central nervous system, and podocytes or tubular cells in the kidney, are particularly susceptible to MC. In the central nervous system, MC has been claimed as the cause of neuronal death in many neurologic disorders, while MC in podocytes and tubular death is connected with the development of progressive glomerulosclerosis.
Keywords
- Mitotic catastrophe
- neuron
- podocyte
- tubular cell
- cell-cycle reentry
1. Introduction
Cell cycle is as old as life itself. In most situations, it is a generative force that creates new cells from old. It is a tightly regulated process whose misregulation can lead to unchecked proliferation and neoplastic disease. Moreover, a decade ago, it was hypothesized that cell-cycle abnormalities may be intimately connected with the death of terminally differentiated cells, such as neurons. In this case, the consequence of cell-cycle alterations is loss of cells, and this phenomenon has been postulated as a mechanism of pathogenesis in several neurodegenerative disorders. Recently, the link between aberrant cell-cycle reentry, cell death, and degenerative diseases has been observed also in other post-mitotic cell types, such as podocytes and tubular cells in the kidney. In this kind of process, post-mitotic cells enter into the cell cycle in response to stress signals in order to substitute death cells, but the absence or malfunction of a specific array of cell-cycle proteins may not allow for its completion. The final result is that the cells can neither reverse the course of the cell cycle or complete division, remaining locked in a non-functional state that push them to trigger a programmed cell death response. Interestingly, in
2. Regulation of the cell cycle
The cell cycle of eukaryotic cells comprises four main successive phases: G1 phase (first gap), S phase (DNA synthesis), G2 phase (second gap), and M phase (mitosis) (Figure 1). The orderly transition from one phase to the following and subsequent progression through the mitotic cycle is controlled by a group of protein kinases whose activity is central to this process, the cyclin-dependent kinases (CDKs). Their levels in the cell remain fairly stable, but each must bind with their activating partners, cyclins, whose levels of expression fluctuate throughout the cycle.
Mitogenic signals, such as soluble growth factors or cell-to-cell contact, stimulate the activation of D-type cyclins and their connection with CDK4 or CDK6. Cyclin D-CDK4 and cyclin D-CDK-6 complexes phosphorylate the retinoblastoma protein (Rb) and inhibit its affinity to bind the transcription factor E2F-1. Thus, E2F-1 is free to induce the transcription of specific genes involved in DNA replication. Moreover, in late G1, inhibition of Rb activates the expression of cyclin E that binds with CDK2. The cyclin E-CDK2 complex ensures the G1/S transition to occur by fully inactivating Rb by hyperphosphorylation. Thus, CDK2 to regulate progression from G1 into S phase. Cyclin A binds with CDK2 that phosphorylates various substrates allowing DNA replication. The formation of cyclin A/CDK2 complex is required during S phase. After completion of S phase, DNA replication ceases and cells enter the G2 phase of the cycle. The cyclin A-CDK1 complex plays a central role in the transition from S to G2/M phase of the cell cycle by regulating the phosphorylation of specific substrates necessary for the completion of the G2 and M phases of the cell cycle. Mitosis is further regulated by cyclin B-CDK1 complex, which appears in late G2 and triggers the G2/M transition. Cyclin A is degraded and the system is reset. In this way, cells are now ready to start a new cell cycle when the presence of mitogenic stimuli induces the upregulation of D-type cyclins.
CDK activity can be counteracted through post-translational modifications and subcellular translocations of specific CDK inhibitors (CDKIs), which bind with CDK alone or to the CDK–cyclin complex. CDKIs are organized in two families: INK4 and Cip/Kip. The INK4 family (inhibitors of cyclin D-dependent kinases) includes four members—p16INK4a, p15INK4b, p18INK4c, and p19INK4d—which specifically inactivate G1 CDK (CDK4 and CDK6) and the Cip/Kip family (inhibitors of cyclin D-, cyclin E-, and cyclin A-dependent kinases) comprises p21Cip1, p27Kip1, and p57Kip2. CDKIs are regulated by both internal and external signals. The intracellular localization of different cell-cycle-regulating proteins also contributes to a correct cell-cycle progression.
Two important checkpoints (G1/S and G2/M) coordinate CDKs activity and ensure that each stage of the cell cycle is correctly completed before allowing further progress through the cycle. If conditions are inadequate, the cell will not be allowed to progress through the cell cycle and be both arrested, until conditions are favorable, or induced to die through apoptosis (reviewed in reference [2]). The G1/S checkpoint, also known as the restriction point in mammalian cells, is defined as a point of no return in G1, following which the cell is committed to enter the cell cycle. It is necessary to control the progression of cell cycle in the presence of DNA damage. At this checkpoint, p53 activity arrests cell cycle induced by DNA damage, stimulating the transcription of different genes including p21. At the G2/M checkpoint, mitotic entry is prevented in response to DNA damage by mechanisms similar to those in the G1/S checkpoint. An additional checkpoint, the mitotic spindle checkpoint, occurs at the point in metaphase where all the chromosomes should have aligned at the mitotic plate and be under bipolar tension.
3. Molecular basis of mitotic catastrophe
“Mitotic catastrophe” has been reported, for the first time, in a temperature-sensitive lethal phenotype of
4. Cell-cycle alterations in post-mitotic neurons
Mature neurons of central nervous system are typically described as permanently post-mitotic cells that have been recently revealed to be in a continuously activated but arrested cell-cycle status. Thus, neurons must constantly keep their cell cycle in check, avoiding its re-initiation, since vigilance relaxation would mean death. During the development, neurogenesis takes place mainly in a tightly packed layer of nuclei lining the lumen of the neural tube (the ventricular zone, VZ) and later in the closely apposed region known as the subventricular zone (SVZ). After birth, the VZ has been depleted of all mitotic cells, but cells with stem cell precursors properties are present throughout the adult brain particularly in the SVZ (to a greater or lesser extent in different vertebrates) and can give rise to neurons in the adult in case of injury. Following the last cell division, neurons mature and the still unclarified mechanisms that will ensure a permanent mitotic arrest begin. What would happen if a neuron lost control of its cell cycle and reentered cell division? Evidence suggests that the neuron would die. One of the first descriptions of this phenomenon was given in 1992 analyzing the effects of expression of SV40 T antigen in Purkinje cells or in photoreceptor. While the expression of this viral oncogene typically promotes tumorigenesis in mammalian cells, its expression in post-mitotic neurons induced the appearance of mitotic figures, and entry in S phase not followed by proliferation but by cell death.[74,75] RB protein has an important role in the maintenance of neuron cell-cycle control and mice deficient in Rb show in the nervous system, ectopic mitoses, and massive neuronal death.[76] Freeman
The involvement of cell-cycle molecules was found also in ALS. Nuclear accumulation of phosphorylated RB protein, with concurrent increase in cytoplasmic levels of cyclin D, and redistribution of E2F-1 into the cytoplasm occur in motor neurons and glia during ALS, suggesting overcoming of G1/S checkpoint during ALS as mechanisms regulating motor neuron death.[95] More recently, Ranganathan
5. Cell-cycle alterations in podocytes
Podocytes are specialized renal epithelial cells that, through cytoplasmic extensions called foot processes, interdigitate with neighboring podocytes and cover the surface of the glomerular capillary loops, thus forming the glomerular filtration barrier (GBM). Podocytes, like neurons, are terminally differentiated post-mitotic cells, with a sophisticated actin cytoskeleton, whose disruption due to genetic, mechanic, immunologic, or toxic injury leads to the detachment of cells from glomerular basement membrane, and finally to podocyte loss. Decrease in the number of podocytes in the glomerular capillary tuft is associated with the development of glomerular sclerosis in several human and experimental diseases. Two cellular strategies that could act to compensate for cell stress or relative cytopenia (e.g., during organogenesis or injury) are hypertrophy, which is an increase in cell size, and hyperplasia, which is an increase in cell number. Both these processes require that quiescent cells reenter the G1 phase to increase the amount of cell organelles and proteins. Podocytes can only undergo hypertrophy, producing additional foot processes to compensate for podocytopenia. Indeed, several protective mechanisms prevent podocyte progression to mitosis and arrest their cell cycle at the restriction points of G1 and G2 phases. The ability of podocytes to arrest at the restriction point is well documented.
Podocyte multinucleation on the other hand is a recognized feature of aberrant mitosis, also described by Nagata
6. Cell-cycle alterations in renal tubular epithelial cells
6.1. G1 arrest
Acute kidney injury (AKI) is a potentially devastating, increasingly common syndrome characterized by rapid impairment of kidney function as a result of a toxic or ischemic insult. In the first 24 h following injury, tubular cells undergo apoptotic and necrotic cell death, and 70% of the surviving, normally quiescent proximal tubule epithelial cells enter the S phase of the cell cycle.[143,144] This is documented by an increase in PCNA,[145–147] incorporation of 3H-thymidine and 5-bromo-2-deoxyuridine into nuclear DNA, and induction of mRNA for “immediate-early” genes, c-fos, c-jun, and egr-1.[148,149] A rapid induction of p21, in several models of AKI, has also been reported.[149] This cell-cycle reentry after injury has traditionally been viewed as an appropriate repair response to the loss of adjacent cells after an initial insult. However, this is in contrast to the observation that cell-cycle inhibition is protective against several form of AKI. The strategic role of p21 in AKI is demonstrated by a series of experiments. Administration of an adenovirus vector directing the expression of p21 protects mouse proximal tubule cells in culture from cisplatin toxicity.[150] Similar results can be obtained by treating cells with several cell-cycle inhibitors, such as roscovitine and olomoucine.[150]
The hypothesis that cell-cycle inhibition post-insult protects against AKI is supported by several experimental findings. As reported above, the cell-cycle-inhibitory drug roscovitine is effective in protecting kidney cells
Thus, following injury, tubular cells enter the cell cycle, but rapidly arrest in the G1 phase. This G1 cell-cycle arrest prevents cells from dividing when the DNA may be damaged and arrests the process of cell division until the damage can be repaired lest resulting in the cell’s demise or senescence. Two inducers of G1 cell-cycle arrest, insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), have been recently identified and their urinary levels serve as sensitive and specific biomarkers to early prediction of AKI and of renal recovery.[160,161] IGFBP7 directly increases the expression of p53 and p21 and TIMP-2 stimulates p27 expression. The upregulated p proteins in turn block cell-cycle promotion acting on the cyclin-dependent protein kinase complexes (CyclD-CDK4 and CyclE-CDK2), thereby inducing G1 cell cycle presumably to avoid cells with possible damage from dividing. Markers of cell-cycle arrest such as TIMP-2 and IGFBP7 may signal that the renal epithelium has been stressed and has shut down various function but may still be able to recover without permanent injury to the organ.[161]
6.2. G2/M arrest
For several decades, AKI was usually assumed to be transient with usual expected recovery of renal function if the individual survived the acute illness. Observational clinical studies and animal models however link AKI to chronic kidney disease (CKD) progression. When kidney injury is of mild entity with normal baseline function, the repair process can be adaptive with few long-term consequences. On the contrary, if injury is more severe, repeated, or to a kidney with underlying disease, the repair can be maladaptive. Maladaptive repair leads to CKD, a process characterized by persistent parenchymal inflammation, with increased numbers of myofibroblasts and accumulation of extracellular matrix (Figure 4). The mechanism that triggers the fibrogenic response after injury is not well understood but a G2/M arrest of tubular cells has been demonstrated being an important driver of maladaptive repair and progressive CKD after AKI.[162–164] Indeed, characterization of the cell-cycle profile of tubular epithelial cells
However, application of these therapeutic strategies in humans needs careful assessment of the safety of the drugs and pathways under investigation because the G2/M checkpoint is extremely important in preventing the perpetuation of dangerous DNA mutations.
A great comprehension of the mechanisms involved in cell-cycle arrest could thus help not only in the discovery of novel therapeutic strategies to prevent podocyte loss, glomerulosclerosis, proteinuria and progressive kidney disease, but also in the selection and utilization of new specific and sensitive biomarkers for AKI.
7. Conclusions
Terminal differentiation invariably involves two closely linked phenomena: permanent withdrawal from the cell cycle and cell type-specific differentiation characterized by the upregulation of a panel of tissue-specific genes. Typically, post-mitotic cells do not reenter the cell cycle when exposed to growth signals, and in some cases further increases in tissue mass are achieved through an increase in cell size or hypertrophy. One long-standing theory to explain the lack of cytokinesis in post-mitotic cells, such as neurons, podocytes, and adult cardiac myocytes, is the presence of highly organized mature myofibrils which physically prevent cell division. Because cells must disassemble their cytoskeletal filaments before entering cell division, disassembly of the cytoarchitecture in these cell types would presumably negatively impact their function. However, in these cells expression of a wide range of cell-cycle proteins has been described, although no cases of cell division have ever been reported. This, together with the finding that the expression of cell-cycle proteins is necessary to execute cell death in response to certain stress signals, has led to the proposition that in post-mitotic cells, cell cycle is part of a well-regulated response to stress signals. The mechanisms by which cell-cycle reentry causes cell death are not completely known, but exploring the trigger(s) that induce normally post-mitotic cells to re-express cell-cycle proteins late in life as well as the molecular mechanism by which the induction of these proteins leads to cell death may produce great advances in the treatment and prevention of several neuro- and renal degenerative diseases.
8. Abbreviations
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