Stress in the EGFR family

 

Lab rotation project description

Protein production is typically switched off when cells are stressed. However, some protein synthesis is required for a cell to mount an appropriate response to stress. Many stress response proteins, when expressed incorrecty, are associated with disease. We recently identified a mechanism by which EGFR (epidermal growth factor receptor) evades the normal stress induced global translation shutdown, and how it can continue to drive proliferation. EGFR is one of a group of related proteins, but less is known about the post-transcriptional regulation of the rest of the family.

 The lab rotation will be delivered as follows:

  • weeks one, two and three: amplification and cloning of EGFR family members into luciferase reporter constructs
  • weeks three, four and five: cell culture, transfection of reporter constructs and assay. The effects of several cell stresses will be compared
  • weeks six and seven: mutagenesis and further hypothesis testing, directed by you based on data obtained

In parallel, you will explore some bioinformatic analysis of EGFR/ErbB/HER DNA/RNA sequences, looking for associations with disease and for conservation of potential regulatory elements. This project is part of a training triangle with a theme of growth factor mediated signal transduction (other supervisors: Cornelia de Moor, Lodewijk Dekker) and all three rotations will contribute to your training for any one of these projects.

Fact file

Research theme

MCO

Location

tbc

Rotation

tbc

Contact

2nd supervisor

Cornelia De Moor 

BBSRC Doctoral Training Partnerships
 

Linked PhD Project Outline

Regulatory elements in the untranslated regions of messenger RNAs allow post-transcriptional responses to cellular stresses and other stimuli. This type of regulation allows cells to respond to stresses, but can also be linked with inappropriate gene expression and disease. However, a better understanding of the regulation of genes associated with disease also allows us to identify novel drug targets and to design improved therapies for proliferative disease. The principle hypothesis is that genes required in the response to cell stresses will be immune to the downregulation of gene expression that typically accompanies cell stresses. This project will use a combination of bioinformatic and laboratory tools to investigate how the EGFR/ErbB/HER family of growth factor receptors respond to cell stresses. You will clone the human genes for these growth factor receptors and use a combination of reporter assays and mutational analysis to identify regulatory elements in the 5’ and 3’ UTRs. You will get training in a broad range of molecular biology techniques, in addition to specialised methods such as polysome profiling. Training in bioinformatic methodologies will add an extra dimension to your research and give you much sought after skills in this rapidly growing area of pharmacy research.

You will be encouraged to design strategies to target the regulatory elements identified in the early part of the project, for example using complementary oligonucleotides. In the unlikely event that no post-transcriptional control is observed in response to stress (which itself will be a notable finding), we will expand the search to include other disease-linked tyrosine kinase receptors.

The project will take place in a well-resourced laboratory shared with several other research groups interested in gene regulation and RNA biology. We foster a supportive and collegial research environment where honest communication and constructive discussions are encouraged, and where expert advice is readily available.

 

Biotechnology and Biological Sciences Doctoral Training Programme

The University of Nottingham
University Park
Nottingham, NG7 2RD

Tel: +44 (0) 115 8466946
Email: bbdtp@nottingham.ac.uk