Mitotic catastrophe can be considered as a type of cell death occurring during mitosis or resulting from mitotic failure. At least two subtypes of mitotic catastrophe can be distinguished. First, mitotic catastrophe can kill the cell during or close to the metaphase, in a p53-independent manner, as this occurs in Chk2-inhibited syncytia or Plk2-depleted cells. Second, mitotic catastrophe can occur after failed mitosis, during the activation of the polyploidy checkpoint, in a partially p53-dependent manner. Mitotic catastrophe is accompanied by chromatin condensation, mitochondrial release of proapoptotic proteins (in particular Cyt. c and AIF), caspase activation and DNA degradation. This implies that mitotic catastrophe is accompanied by the key molecular events defining apoptosis, namely, capase activation and MMP.
Mitotic catastroph can also be defined as an aberrant form of mitosis associated with the formation of multinucleate giant cells that are temporarily viable but reproductively dead. Mitotic catastrophe is pre-determined in G2 and characterised by an abortive short cut into metaphase arrest. Mitotic failure often manifests with micro nucleation and nuclear segmentation and this in turn, is associated with mitosis restitution into interphase polyploid cells Mitotic catastrophe has been described as an aberrant form of mitosis associated with various morphological and biochemical changes. The final step of mitotic catastroph is almost always characterized by the formation of nuclear envelopes around individual clusters of miss aggregated chromosomes. It is also correlated with incomplete DNA synthesis and premature chromosome condensation (PCC).
Get your grade
or your money back
using our Essay Writing Service!
Mitotic catastrophe has also been described as a delayed form of reproductive death based on observations that the multinucleated giant cells can be temporarily viable. The term 'reproductive death' denotes the loss of the ability of a cell to generate viable progeny that reproduced continuously. As most of the cells undergoing mitotic catastroph eventually die, cellular processes that lead to irreversible growth arrest and those that are termed 'reproductive death' may better fit to conditions known as senescence. Mitotic catastroph shares several biochemical hallmarks with apoptosis, namely mitochondrial membrane permeabilization and caspase activation.
Mitotic catastrophe is the response of mammalian cells to mitotic DNA damage. It produces tetraploid cells with a range of different nuclear morphologies from binucleated to multi micronucleated. In response to DNA damage, checkpoints are activated to delay cell cycle progression and to coordinate repair. Mitotic catastrophe' of mammalian cells as the failure to undergo complete mitosis (which would be more accurately called 'mitotic failure') after DNA damage (coupled to defective checkpoints), a situation that would lead to tetraploidy (after a single cell cycle) or endopolyploidy (after several cell cycles) with extensive DNA damage and repair, perhaps followed by the selection of apoptosis-resistance cells that will ultimately survive after endo reduplication.
The potential factors which regulate the process of mitotic catastroph are - damage to the DNA, defects in the mitosis, premature mitosis due to genotoxic insult, defects in the cell check points, defects in cellular spindle assembly, death of giant cells, defects in the chromatin condensation and abberent mitosis
During recent years, the expression of 'mitotic catastrophe' has been widely used to describe a form of death affecting mammalian cells. Defining mitotic catastrophe in morphological terms, namely, as a type of cell death resulting from abnormal mitosis, which usually ends in the formation of large cells with multiple micronuclei and decondensed chromatin. Mitotic catastrophe' frequently show cells with some phenotypic characteristic of apoptosis (such as hypercondensed chromatin aggregates), which previously often was interpreted as 'premature chromatin condensation.
Mitotic catastrophe would be a type of cell death occurring during mitosis, as a result of DNA damage or deranged spindle formation coupled to the debilitation of different checkpoint mechanisms that would normally arrest progression into mitosis and hence suppress catastrophic events until repair has been achieved.
The 'DNA structure checkpoint' arrests cells at the G2/M transition in response to unreplicated DNA or DNA damage, and the 'spindle assembly checkpoint' prevents anaphase until all chromosomes have obtained bipolar attachment. The combination of checkpoint deficiencies and specific types of damage would lead to mitotic catastrophe. Thus, the pharmacological inhibition or genetic suppression of several G2 checkpoint genes such as ATM, ATR, Chk1, Chk2, polo-like kinase (Plk)1, Plk2, Plk3, Pin1, Mlh1 and 14-3-3-s can promote DNA-damage-induced mitotic catastrophe. Mitotic catastrophe can also be induced by fusion of mitotic cells with interphase cells in S or G2, as a result of premature induction of mitosis before the completion of S or G2. Over duplication of centrosomes (which leads to multipolar mitosis) or failure of centrosomes to undergo duplication (with consequent failure of chromosomes to segregate) may also lead to mitotic catastrophe.
Always on Time
Marked to Standard
Study conducted by Huang et al.2004 reported the presence of a mitotic exit DNA damage checkpoint in mammalian cells. This checkpoint delays mitotic exit and prevents cytokinesis and, thereby, is responsible for mitotic catastrophe. The DNA damage-induced mitotic exit delay correlates with the inhibition of Cdh1 activation and the attenuated degradation of cyclin B1. They demonstrate that the checkpoint is Chk1-dependent.
The study conducted by Ngan et al.,2008 examined the cytotoxic effects of oxaliplatin in vitro, using two esophageal cancer cell lines: one derived from SCC (cell line TE3) and one from ADC (cell line TE7). Specifically, they investigated the underlying mechanism in oxaliplatin-induced growth inhibition and cell death. Cisplatin was included as a control. The effect of oxaliplatin on two esophageal cancer cell lines that is squamous cell carcinoma (TE3) and adenocarcinoma (TE7) was studied. Following cell-cycle arrest at G2 phase after oxaliplatin treatment, TE3 cells died via apoptosis and TE7 cells died via mitotic catastrophe. The treatment with oxaliplatin in TE7 cells introduced more death by mitotic catastrophe showing presence of two or more nuclei in the cells. The TE3 cell lines undergo apoptosis by showing the condensation of chromatin, nuclear fragmentation and shrunken cells. Cells that displayed features indicative of mitotic catastrophe, namely cells with two or more evenly stained nuclear fragments, following oxaliplatin and cisplatin treatment was counted. Both drugs induced a higher rate of mitotic catastrophe in TE7 compared to TE3. Another distinct feature observed in the oxaliplatin-treated TE7 cells was nuclear enlargement. Although these cells had single nuclei, the nuclei were gigantic compared with the control cells. Cells with nuclear enlargement were defined as containing a single nucleus with a diameter 1.5-fold larger than the mean diameter of nuclei of control cells. After treatment with oxaliplatin, a gradual increase was observed in the percentage of TE7 cells with enlarged nuclei: 11.1% at 24 h, 21.3% at 48 h, and 35.6% at 72 h. To gain insights into the molecular mechanisms responsible for the growth inhibition and mitotic catastrophe events observed following oxaliplatin treatment, they analyzed the expression of cell-cycle regulatory proteins, namely p21waf1/cip1, cdc2 and several proteins that are shown to be associated with mitotic catastrophe, namely, 14-3-3σ, aurora kinases, and surviving. The expression of p21waf1/cip1 was downregulated strongly in both cell lines following oxaliplatin treatment. A decrease in the expression of 14-3-3σ was evident in TE7 cells following oxaliplatin treatment. Downregulation of aurora A kinase and a slight decrease in aurora B kinase were also noted in both cell lines. In the study, it was also found that the inhibition of survivin caused the mitotic catastroph.