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Title: Identification and characterisation of a novel p21 feedback loop in the regulation of p53
Author: Pang, L. Y.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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A key transcriptional target of p53 is the cyclin-dependent kinase inhibitor, p21WAF1/CIP1 (hereafter referred to as p21), which mediates p53-dependent G1 arrest. There is a growing list of human carcinomas that have aberrant p21 expression. p21-null animals also have elevated tumour incidence. Our data identifies p21 as a component of a positive feedback loop that maintains the p53 transcriptional response. three model systems were used to characterise this novel mechanism of p53 regulation. In the human colon carcinoma cell line HCT116 with targeted inactivation of p21, p53 stabilisation is uncoupled from its activity of a transcription factor and shows defects in the p53 response to DNA damage and double stranded RNA, indicating that a common mechanism prevents p53 activation by distinct stresses in the absence of p21. The p53 transcriptional programme in response to cellular damage can be reactivated after complementation of the p21 gene into the HCT116 p21-null cells. In B-cells from mice lacking the p21 gene, a striking loss of the p53-dependent transcription programme was identified using p53-specific microarray screens. Gene dosage effects indicate a progressive loss of p53 function in B-cells heterozygous or homozygous null for p21. Similarly, siRNA to p21 can attenuate the p53-depdnent transcription response in normal human fibroblasts. In all three model systems, deletion of the p21 gene results in p53 nuclear export and eliminates the p53 transcriptional response. this data indicates that p53 has evolved a co-ordinated transcription mechanism to control its own function: a positive feedback loop maintained by p21 and a negative feedback loop maintained by MDM2, whose balance controls the specific activity of p53.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available