MASTL overexpression promotes chromosome instability and metastasis in breast cancer.

MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial-mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival

MASTL overexpression promotes chromosome instability and metastasis in breast cancer

MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial-mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival

Optimising stand density and nitrogen fertiliser rates for seed production in the tetraploid italian ryegrass cultivar K29T

Tetraploid cultivars of Italian ryegrass have been developed and used as an alternative to diploid cultivars in an attempt to improve forage yield and quality. But, very often, production of tetraploid cultivars is reduced by unfavourable weather conditions. The objective of this research was to determine seed production stability of the tetraploid Italian ryegrass cultivar K29T in variable and contrasting environmental and meteorological conditions in Serbia. The study was conducted in four consecutive years and generations of seed multiplication. Every year, seed was harvested from the primary growth in the first production year after the year of establishment. Data of investigated traits (heading and harvest dates, tiller length, number of spikelets per spike, seed yield, dry herbage yield and 1,000 seed weight) were recorded for different management practices (stand densities and nitrogen applications). It was determined that seed yield, dry matter production and tiller length were presumably most affected by different environmental factors in different production years, and different management practice, especially different sowing densities. In contrast, number of spikelets per spike and 1,000 seed weight were less affected by management practice, except in the extremely arid 2003 year. Variation in seed yield was more related to variation in seed numbers than to variation in seed weight. In the first seed production year, the best density in this experiment was 15-20 kg ha−1 of seed sown at an interrow spacing of 60 cm without fertilizing or with only 50 kg ha−1 of N. Therefore, seed of tetraploid Italian ryegrass cv. K29T can be produced in diverse environmental conditions in Serbia, but lower stand densities allow for better plant tillering and the production of a greater volume of seed and, at the same time, good dry matter yield of the residual biomass