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Title: Regulation of the DNA damage response gene GADD45a
Author: Johnson, Donna
ISNI:       0000 0004 2668 4949
Current Institution: University of Manchester
Date of Award: 2008
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The published validation study of a new in vitro mammalian test, GreenScreen HC, has shown it to be both highly specific and highly sensitive in the detection of genotoxic carcinogenicity, with values higher than those for many of the regulatory genotoxicity tests. This test has great potential to fill a need for a new pre-regulatory test that is easier, cheaper and quicker to perform, while still being predictive of rodent carcinogenicity. In this thesis experimentation fell into three groups - investigation of compounds with positive results in one or more regulatory mammalian in vivo tests; testing of compounds with little or contradictory regulatory genotoxicity data and investigation into the effect of the GADD45a regulatory elements included within the reporter plasmid. The testing of false positive compounds showed GreenScreen HC to be second only to the MNT test for specificity and confirmed previously published data stating the high levels of specificity of GreenScreen HC. Testing of groups of compounds with little genotoxicity data highlighted genotoxic potential for a number of compounds including a number of the histone deacetylase inhibitors and the synthetic retinoid CD437. The effect of the regulatory elements included in the assay were investigated through use of reporters with mutated response elements. With each mutation, the induction of GADD45a was lessened and this highlighted the importance of the use of cells with fully component DNA damage response pathways for genotoxicity testing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available