Targeting mitotic pathways for endocrine-related cancer therapeutics
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Figure 1
A schematic representation of cell cycle progression and the crucial components that are currently targeted at the various stages or can be exploited in the future for anti-cancer therapy. (1) The ORC, Cdc6 and Cdt1 assemble to form the pre-replicative complex (pre-RC) necessary to load the presumptive MCM replicative helicase, a process called as replication licensing. From late mitotic phase (M) to G1 phase, two critical inhibitors of the pre-RC formation, Cdk and geminin are suppressed by APC/C ubiquitin ligase that targets them for proteolysis through polyubiquitination (Fujita 2006). At the onset of S-phase, Cdk becomes active (by APC/C inactivation) and functions to obliterate the re-establishment of pre-RC and re-licensing during the S, G2 and M phases of the cell cycle (Fujita 2006). This is accomplished by Cdk-mediated phosphorylation of Cdc6 followed by its nuclear export, phosphorylation and degradation of ORC and Cdt1 (Fujita 2006). After S-phase, geminin also accumulates that sequesters Cdt1 by direct binding. Cdt1 however re-accumulates post G2-/M-phase in phosphorylated state where it contributes in maintaining robust kMT attachments via its interaction with the Hec1 loop. (2) The kinetochore proteins start to assemble through the recognition of centromeres enriched with the CENP-A (centromere-associated protein-A) containing nucleosomes that marks it as the site for kinetochore formation. In early prometaphase or prophase, the KMN network, especially the Knl1 protein along with Zwint-1 serves to recruit several checkpoint proteins like Mad1, Mad2, Mps1 kinase, Bub1, Bub3, the RZZ complex, BubR1 and CENP-E to the unattached kinetochores for rapid generation of ‘wait-anaphase’ signal until every single KT pair achieves bi-orientation. This active SAC (‘on-state’) inhibits the anaphase-promoting complex/cyclosome (APC/C) activator Cdc20 (cell-division-cycle 20). Note that Ska binds to the Hec1 loop and its phosphorylation by Aurora B kinase subsequently abrogates its interaction with the KMN network. (3) Upon appropriate error-free kMT end-on attachments, Aurora B activates Plk1 that induces PP2A binding to BUBR1 causing the dephosphorylation of the RVSF/SILK motifs, thereby allowing PP1 to bind and act on Knl1. The binding of PP1 dephosphorylates the MELT repeats and the SAC components are released from the KMN network, extinguishing the SAC to an ‘off’ state. Microtubules and its associated proteins like MAPs and motor proteins are depicted. (4) After the SAC is satisfied and its components are removed from the kinetochore, APC/C regains its activity to degrade securin and cyclin B1 that triggers anaphase and exit from mitosis. Separase, a protease that cleaves the cohesins that hold sister chromatids together, is inhibited by binding to securin. But upon securin degradation, separase is released to cleave cohesin and allow the sister chromatids to undergo separation in anaphase.
- © 2017 Society for Endocrinology
