The Role of the Mitotic Spindle Checkpoint in Chemotherapy-Induced Apoptosis

Celia Vogel, Molekularbiologie Und Tumorforschung, Bastians, Holger (Dr.)
2011
The mitotic spindle assembly checkpoint (SCP) is a signal transduction pathway that ensures proper chromosome segregation during mitosis by inhibiting the onset of anaphase until all chromosomes are properly aligned. It requires a group of highly conserved proteins including Mad1, Mad2, Bub1, BubR1, Mps1 and the so-called chromosomal passenger complex comprising survivin, borealin, INCENP and the Aurora B kinase. The SCP ensures chromosomal stability during a normal mitosis, but it is also
more » ... ated by chemotherapeutic drugs that interfere with chromosome alignment leading to a prolonged mitotic arrest. Subsequently tetraploid cells exit mitosis – a process termed "mitotic slippage"–, thereby activating the so-called pseudo-G1 checkpoint, which arrests cells p53-dependently at the G1/S border. Failure of this second fail-safe mechanism might promote cancerogenesis via polyploidization and induction of genomic instability. The present work has defined the pseudo-G1 checkpoint as dependent on p53 and a functional SCP. Moreover, an additional SCP-independent checkpoint is activated in G2, which prevents polyploid cells from entering the next mitosis. Thus, multiple checkpoints cooperate to prevent further polyploidization after mitotic failure. Antimitotic substances are among the most frequently used chemotherapeutics. However, the mechanisms of mitosis-associated apoptosis and chemotherapy resistance are largely unknown. During the course of my work I demonstrated that the SCP is required for the induction of apoptosis in response to various antimitotic drugs. Specifically, Mad2 was shown to be a central proapoptotic factor after treatment with drugs that impair kinetochore tension, which do not only include spindle poisons like taxol, but surprisingly also DNA damaging agents like topoisomerase II inhibitors. A clinically relevant mitosis-associated chemotherapeutic strategy is the induction of "mitotic catastrophe", a poorly defined form of cell death. Abrogation of the activated G2 DNA damage checkpoint by Chk1 [...]
doi:10.17192/z2009.0103 fatcat:i6dawnevefgmdnhgow4wigtjli