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The role of CBP and p300 in cardiac hypertrophy

Gusterson, Rosalind Jane; (2002) The role of CBP and p300 in cardiac hypertrophy. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The closely related CBP and p300 co-activator molecules play a key role in gene activation by interacting with a number of different transcription factors, and have been shown to be essential for normal cardiac development and expression of genes encoding cardiac muscle-specific proteins. Evidence from non-cardiac cells also indicates that these factors are essential for the proper functioning of transcription factors known to be involved in cardiac hypertrophy. Hypertrophy is initially a compensatory response in the heart, defined by enlargement of cells without division and reactivation of foetal genes. Chronic hypertrophy can be detrimental and may lead to heart failure. The subject of this thesis is an investigation of the role of CBP and p300 in cardiac hypertrophy. Phenylephrine (PE) is an a-adrenergic agonist known to induce hypertrophy in cardiac myocytes. Here it is shown that in cardiac cells the activity of CBP and p300 is stimulated by PE treatment by a mechanism which involves the p42/p44 MAPK pathway, targeting primarily the N-terminus of p300 and the C-terminus of CBP which are not homologous to one another. This suggests that CBP and p300 play an important role in the hypertrophic effect of PE. To further support this theory, data here shows that inhibition of either CBP or p300 with antisense or dominant negative mutant constructs inhibits PE-induced hypertrophy as assayed by atrial naturetic protein production (ANP), cardiac cell protein:DNA ratio and cell size. In view of the critical clinical importance of hypertrophy in human heart failure, work here has attempted to probe the mechanisms by which CBP and p300 can induce hypertrophy, and in particular, to relate them to their known histone acetyltransferase activity. Results show that the ability of CBP and p300 to induce hypertrophy is dependent upon their histone acetyltransferase activity since inhibition of histone deacetylation using trichostatin A can induce hypertrophy, and mutations in CBP or p300 which abolish or reduce such activity correspondingly abolish or reduce the ability to induce hypertrophy, as assayed by ANP production, protein:DNA ratio and cell size. In summary, this work demonstrates that CBP and p300 play a key role in the PE-induced hypertrophic response and that this effect is dependent on their histone acetyltransferase activity. These findings raise the possibility therefore that CBP and p300 represent targets for therapeutic modulation in the control of human heart failure caused by cardiac hypertrophy.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of CBP and p300 in cardiac hypertrophy
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Heart failure
URI: https://discovery.ucl.ac.uk/id/eprint/10102240
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