Validating Greatwall kinase as a potential target in cancer therapy

All cancers have deregulated cell proliferation. Therefore, full understanding of cell cycle control is needed to identify protein targets that can lead to the development of novel therapies, as well as improving our knowledge and use of existing ones. Greatwall kinase (GWL), a protein essential for mitotic entry in human cells, is gaining interest in cancer research as it has been shown to be upregulated in various cancers. My research aims to decipher the mechanisms of Triple Negative breast cancer (TNBC) cell sensitivity to GWL knockdown, as this information could provide scope for the development of novel drugs to be synergised with existing treatments. We have shown that depletion of GWL via shRNA in certain TNBC cell lines causes harmful cell proliferation defects. Surprisingly these effects coincided with significant depletion of replicating cells, rather than pronounced mitotic defects. This suggests that certain cancer cells are especially reliant on GWL and that GWL may have other functions apart from its known role in suppressing mitotic PP2A activity. To further investigate these novel functions, we have performed a siRNA cell viability screen comparing cells lacking and expressing GWL. This led to the identification of a novel synthetic lethality between CDK4 (a kinase whose activity is restricted to G1-S phase) and GWL (canonically active in mitosis). Further analysis revealed that this synergy of GWL and CDK4 does not involve the known downstream substrates of GWL: ENSA and ARPP19, suggesting that GWL acts in this pathway in a non-canonical way. Taken together, this thesis presents the discovery of a novel biological pathway in the control of the G1/S transition that could be exploited in cancer therapy to treat TNBC patients

Figure S1: Supplemental images of TGFβ2 KO coloboma phenotypes from TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism

(A) Serial frontal sections (E18.5, H&E) of a TGFβ2 KO embryo from mixed genetic background. The optic fissure margins did not fuse but grew inwards. Scale bars represent 200µm. (B) Serial frontal sections (E18.5, H&E) of a TGFβ2 KO embryo from mixed genetic background. In addition to the usual coloboma phenotype, there is a dorsal coloboma. Scale bars represent 200µm. (C) Serial frontal sections (E18.5, H&E) of a TGFβ2/GDNF double KO embryo. In addition to the usual coloboma phenotype, there is a dorsal coloboma. Scale bars represent 200µm.ted fish as control

Figure S2: Establishment of a TGF signalling reporter in zebrafish from TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism

(A) Construct for the TGFβ signalling reporter. Multimerised Smad Binding Elements (SBEs) in combination with a minimal promoter (MP) drive membrane localised GFP (GFPcaax). (B) Bright field, fluorescent and merged images of a zebrafish larva expressing the TGFβ signalling reporter construct (21.5 hpf). Note the expression domains in the forebrain (encircled) and the tail. (C) SB431542 reduces TGFβ reporter activity, DMSO treated fish as control. Treatment was administered from 24 hpf to 48 hpf. The inhibitor was renewed during the time of the treatment

Data from: Pan-Atlantic analysis of the overlap of a highly migratory species, the leatherback turtle, with pelagic longline fisheries

Large oceanic migrants play important roles in ecosystems, yet many species are of conservation concern as a result of anthropogenic threats, of which incidental capture by fisheries is frequently identified. The last large populations of the leatherback turtle, Dermochelys coriacea, occur in the Atlantic Ocean, but interactions with industrial fisheries could jeopardize recent positive population trends, making bycatch mitigation a priority. Here, we perform the first pan-Atlantic analysis of spatio-temporal distribution of the leatherback turtle and ascertain overlap with longline fishing effort. Data suggest that the Atlantic probably consists of two regional management units: northern and southern (the latter including turtles breeding in South Africa). Although turtles and fisheries show highly diverse distributions, we highlight nine areas of high susceptibility to potential bycatch (four in the northern Atlantic and five in the southern/equatorial Atlantic) that are worthy of further targeted investigation and mitigation. These are reinforced by reports of leatherback bycatch at eight of these sites. International collaborative efforts are needed, especially from nations hosting regions where susceptibility to bycatch is likely to be high within their exclusive economic zone (northern Atlantic: Cape Verde, Gambia, Guinea Bissau, Mauritania, Senegal, Spain, USA and Western Sahara; southern Atlantic: Angola, Brazil, Namibia and UK) and from nations fishing in these high-susceptibility areas, including those located in international waters

Shapefiles of Figs 1 and 2 and Supplementary figures S1 to S6

The folder includes all the ArcGIS shapefiles used to make figures 1 and 2 and supplementary figures S1 to S6. An excel file is also included which describes which field of which shapefile was used to make which figure

Open Letter to The American Association for the Advancement of Science

This is an open letter concerning the recent launch of the new open access journal, Science Advances. In addition to the welcome diversification in journal choices for authors looking for open access venues, there are many positive aspects of Science Advances: its broad STEM scope, its interest in cross-disciplinary research, and the offering of fee waivers. While we welcome the commitment of the Association to open access, we are also deeply concerned with the specific approach. Herein, we outline a number of suggestions that are in line with both the current direction that scholarly publishing is taking and the needs expressed by the open access community, which this journal aims to serve