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Title: The involvement of NPM1 in transcriptional activation of PCNA
Authors: Chiu, Ya Ming
Degree: Ph.D.
Issue Date: 2012
Abstract: Nucleophosmin (NPM/B23, NPM1) is an important nucleolar phosphoprotein with pleiotropic functions involving in a board range of cellular processes such as ribosome biogenesis, transcription regulation and cell cycle regulation. Our previous results have shown that NPM/B23 plays an important role in resistance to UV-induced cell death by up-regulating PCNA through YY1 and thereby enhancing nucleotide excision repair (NER) activity (Weng and Yung, 2005; Wu and Yung, 2002). However, the underlying mechanism of this process is still unclear. Here we show that NPM/B23 drives PCNA promoter activity depending on its acetylation state. NPM/B23 cooperates with the transcription factor YY1 at an upstream YY1 binding site and regulates the PCNA promoter. The treatment by UV irradiation increased expression level and acetylation state of NPM/B23, and this alteration was accompanied by an increase in PCNA. Additionally, the p300 was bound to PCNA promoter and enhanced the recruitment of NPM/B23 and YY1 to promoter upon UV irradiation. p300 is a transcription co-activator with intrinsic histone acetyltransferase (HAT) activity. Therefore, the PCNA promoter activity in p300 knockdown condition and in NPM/B23 deacetylation-mimicking mutants was examined as compared to wild-type. At 48 h after the addition of p300 shRNA, PCNA promoter activity was significantly decreased (P<0.05). NPM/B23 deacetylation-mimicking mutants which defects in p300 HAT activity, the PCNA promoter activity and subsequently, DNA repair capacity was decreased after UV treatment. These results demonstrate that p300 is importantly participated in PCNA up-regulation by triggering NPM/B23 acetylation. Taken together, we anticipate our findings may be a starting point for anti-cancer treatment. A combination therapy with NPM/B23 antisense and HAT inhibitor to impair the expression level and the acetylation state of NPM/B23 could be a novel therapeutic strategy for preventing recurrence and drug resistance.
Subjects: DNA-protein interactions.
Nuclear proteins -- genetics.
DNA replication.
Hong Kong Polytechnic University -- Dissertations
Pages: xii, 185 leaves : ill. (some col.) ; 30 cm.
Appears in Collections:Thesis

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