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Title: Components of the Ret oncogene signalling pathway
Author: Buchanan, V. S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1999
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The Multiple Endocrine Neoplasia type 2 syndromes are dominantly inherited cancer syndromes of tumour formation (affecting the thyroid C-cells, the adrenal chromaffin cells and the parathyroids) and developmental abnormalities. Germline activating mutations in the ret proto-oncogene, encoding a receptor tyrosine kinase (RTK), have previously been shown to predispose to MEN 2. In order to understand how Ret mutations cause MEN 2, it is important to understand the biology of Ret, including the signal transduction pathways recruited by both the normal and mutant Ret receptors. I have attempted to identify signalling proteins activated by Ret using two approaches. Firstly, the yeast 2-hybrid system was used to screen an expression library with the intracellular domains of both wild-type and MEN 2B Ret, in order to identify interacting proteins. The unreliability of the screen may have resulted from the Ret fusion proteins used being capable of weak activation of the 2-hybrid reporter genes in the absence of an interacting partner. Secondly, protein tyrosine phosphatases (PTPs) were chosen as candidates to interact with Ret. The population of PTPs expressed in tissues affected by MEN 2 (adrenal gland and a C-cell tumour cell line) was examined by degenerate RT-PCR of conserved phosphate domains. Five PTPs (PTPγ, LAR, PTPβ, SHP1 and SHP2) whose expression were detected were chosen as potential modulators of Ret and studied further. SHP1 and Ret expression studies on neural cell lines indicated that the PC12, Neuro 2A and SH-SY-5Y cell lines might be suitable for further signalling studies on SHP1 and Ret. NT cells would also be suitable if an efficient method of transfection could be found.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available