p53 is a transcription factor and tumour suppressor. P53 is mutated in more than half of all human cancers. Mutations result in loss of p53 expression or the expression of a mutated form of p53 (mutant p53). Mutant p53 proteins lose most if not all of the WT function. What is more, these mutants often acquire new functions that make them more able to withstand chemotherapy and promote invasion and metastasis. We have discovered that RCP (Rab11-FIP1) plays a pivotal role in these functions. RCP directs how fast cell surface molecules return back to the plasma membrane in response to external stimuli. We have seen that integrins, growth factor receptors, but also drug transporters can be regulated by RCP. A big question we have is how RCP coordinates the regulation of so many molecules at the same time. How is RCP regulated and which other molecules does it regulate or interact with to promote the gain-of-function of mutant p53 will be the central questions in this project.
Aims:
1. Determine RCP modifications in response to different stimuli
2. Determine changes in RCP interaction partners to different stimuli
3. Determine how these modifications and interaction partners affect RCP and mutant p53 functions by generating versions of RCP that cannot be modified or lose interactions with its partners.
4. Validate findings in vivo in animal models and/or human tissues
Techniques you will learn:
Cell culture, cloning and plasmid isolation, transfection methods, immune fluorescence, various imaging techniques including live cell imaging, immune precipitations, ELISA, CRISPR knockout, animal work (mice), mass spectrometry and omics approaches, cell signaling (phosphorylation)
We are seeking a highly motivated individual who has an interest in molecular imaging of cells and would like to research signaling pathways in oncology to join our lab in Durham University.
Lab website:
https://www.durham.ac.uk/staff/patricia-muller/
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