Transcription and cell cycle control

France, Stephen Andrew (2000) Transcription and cell cycle control. PhD thesis, University of Glasgow.

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Abstract

The antiproliferative effects of the tumour suppressor p53 stem from its ability to induce either cell cycle arrest or apoptosis and are regulated by the p300/CBP transcriptional co-activator proteins. In order to elucidate the mechanisms of p300 dependent transcriptional activation of the p53 response, the role of a newly identified protein co-factor, termed JMY, that physically associates with p300 was examined. JMY effectively assists p300 in p53-dependent transactivation of apoptotic promoting genes. Removal of the proline rich domain in the C-terminus of JMY produces a protein that switches the functional outcome of the p53 response from apoptosis to cell cycle arrest. Results presented here suggest that JMY collaborates with p300 to stimulate p53 apoptosis while the JMYDeltaP isoform collaborates with p300 to induce p53 transactivation of p21[Wafl/Cip1] and cell cycle arrest. Thus, the proline rich region of JMY modulates p53's role as a cell cycle arrest or apoptotic inducing protein. Furthermore, JMY may functionally impact on the p53 pathway through its ability to associate with and influence the activities of human p14[ARF]. JMY co-activates and assists p300 in E2F-1 mediated expression of p14[arf]. In addition JMY is present in the p14[ARF] complex and a functional consequence of the interaction is the displacing of the nucleolar population of p14[ARF] into the nucleoplasm. A tumour derived mutant of pRb, pRbDelta22, that has lost E2F regulatory activity collaborates with JMY in the co-activation of p53-dependent Bax expression, suggesting that cells can by-pass the loss of growth control through pRb by stimulating apoptosis. JMY therefore acts as a potential regulator of the p53 response and may represent a novel target for the development of therapeutically useful modulators of p53 activity. Defining the mechanism through which JMY and pRb collaborate in apoptosis may prove useful in the understanding of the cells response to tumourigenesis.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Nick La Thangue
Keywords: Molecular biology
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-72010
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 13:26
Last Modified: 17 May 2019 13:26
URI: http://theses.gla.ac.uk/id/eprint/72010

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