Date, Kathryn Louise (2012)
Ph.D. thesis, University of Birmingham.
In addition to its essential roles in the maintenance, replication and transcription of the EBV genome, EBNA1 has more recently been shown to influence the transcription of cellular genes and to modulate the activity of key cellular signalling pathways. EBNA1 has previously been shown to abrogate TGFβ signalling in carcinoma cell lines, although the exact mechanism remains to be elucidated. This study has endeavoured to further dissect this observation, whilst revealing a novel function for EBNA1 in the activation of the closely-related BMP signalling pathway. The observed abrogation of canonical TGFβ signalling is now proposed to be the result of an EBNA1-mediated induction of negative regulators, while a concomitant increase in secreted TGFβ, in combination with a shift towards linker region phosphorylation of the R-Smad proteins in EBNA1-expressing cells conceivably constitutes a method of promoting pro-tumourigenic TGFβ-mediated effects, such as cellular migration. In addition, results demonstrating the activation of BMP signalling upon the expression of EBNA1, and in EBV-positive cell lines, are also indicative of a role in the promotion of migration, and potentially metastasis. In this way, EBNA1 may mediate effects that contribute to the development of EBV-associated tumours.
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