*BBSRC EASTBIO Programme* Development of a microscopy-based method for monitoring domain flexibility of macromolecular complexes in living cells

The biological activities of macromolecular complexes involve dynamic movements of their domains or subunits, but the kinetics of such motions in the cellular environment are mostly unknown due the lack of suitable approaches. This project aims to develop a microscopy-based method that monitors changes in domain flexibility in real time in live cells.

Telomere interactions and signaling during the cell division cycle

Telomeres are formed by specific DNA sequences at the ends of the chromosomes and their shortening during cell division plays an important role in limiting proliferation. Recently, it has become apparent that telomere signaling can also be induced in cancer cells delayed in mitosis, leading to activation of the ATM kinase and subsequent activation of the p53 tumor suppressor (Hayashi et al, 2012). This response can be induced by drugs such as taxol (paclitaxel) that inhibit progression through mitosis.

The RNA helicase p68 (DDX5) as a selective modulator of the p53 response to chemotherapy

Breast cancer patients who are treated with chemotherapy show a huge variability in their response. Chemotherapy often results in undesirable side effects that can reduce quality of life and lead to life threating complications. Therefore, identifying patients who will benefit from chemotherapy remains a major research challenge. The p53 tumour suppressor plays a key role in the response to chemotherapy and is frequently mutated in many cancers.

DDX5 lncRNA and encoded miRNAs- potential roles in cell motility and invasion and implications in Melanoma

Background : The RNA helicase p68 is an important transcriptional coactivator of several proteins that play key roles in cancer development. p68 is aberrantly expressed/modified in several cancers, suggesting that alteration in p68 expression/function may be key events in tumour development.

Probing the function of individual Cyclin/Cdk complexes during the cell cycle

Background: Cyclin subunits, in combination with their Cyclin-dependent kinase (Cdk) domains, regulate many aspects of cell cycle progression, including DNA replication (Cyclin A2) and cell division (Cyclin B1). Cyclin A2 and Cyclin B1 share the same catalytic subunits, Cdk1 and Cdk2, therefore it is difficult to separate their functions because Cdk1 or Cdk2 inhibitors affect multiple Cyclin/Cdk complexes at once. For example, Cyclin B/Cdk1 is known to stimulate mitotic entry but Cyclin A2/Cdk1 could well play an important undiscovered role.

Targeting Wnt Signalling in Skin Cancer

Wnt signalling was first discovered in tumour models and has been recognized as a key regulator in cancer for several decades. This has prompted a number of researchers and pharmaceutical companies to develop Wnt-modulating drugs for cancer treatment. However, we are still learning about the complex and often context-dependent effects of WNT signalling in differing tumour types, so it is important to understand the role of Wnt signalling in individual cancers before Wnt-modulating therapeutics can be used to treat patients.

MRI Assessment of Lesion heterogeneity with textural analysis in patients with breast cancer

Tumour heterogeneity, as measured in various imaging modalities including MRI, has been reported to useful in prognostication and in the identification of patients who will achieve a complete response to neoadjuvant chemotherapy (NAC). Heterogeneity considers microscopic image ‘texture’, by mapping and modelling grey-level distributions of individual pixels within regions of interest; textural analysis (TA). It has been hypothesised that TA indirectly links to lesion pathology via tissue structure, which influences the contrast in the final MR image.

Identification of genes involved in F. nucleatum virulence & investigation of the response of eukaryotic cells to invasion

Background: The term ‘Periodontal disease’ is applied to a range of pathological changes to periodontal tissue. Our best understanding of this multi-factorial disease places a key role on microbial communities and central to these communities are Fusiform bacteria such as Fusobacterium nucleatum (FN). These long filamentous organisms are unparalleled in their ability to adhere to a range of different oral bacteria, and have been shown to invade epithelial cells (Edwards et al., 2006). Recent in vivo studies have also demonstrated invasion of the placenta and colon tumours.

TGF-beta signalling in cancer stem cells and metastasis

TGF-beta can act as both a potent tumour promoter and tumour suppressor in a context dependent fashion. During cancer progression tumour cells can modify their response to TGF-beta from anti-proliferative to pro-tumourigenic whereby they can utilise TGF-beta to promote tumour cell proliferation, survival, motility, invasion, intravasation, extravasation, metastatic colonisation and promotion of cancer stem cell straits.


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