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Investigating the Mechanism of p53 Repression of Gfi1 and the Mechanism of Gfi1 Involvement in Lymphomagenesis
Table of Contents
Abstract
Acknowledgements
Table of Contents
List of Figures
List of Abbreviations
1 Introduction
1.1 Hematopoiesis
1.2 Hematopoietic malignancies
1.3 Hematopoietic cytokines
1.4 Hematopoietic transcription factors
1.5 Growth factor independent 1 (Gfi1)
1.6 c-Myc
1.7 The tumor suppressor p53
1.8 Bcl-2 family members in apoptosis
2 Material and Methods
2.1 Cells and materials
2.2 Construction of plasmids
2.3 Transfection and generation of stable cell lines
2.4 Cell proliferation assay (MTS assay)
2.5 Chromatin immunoprecipitation assay (ChIP assay)
2.6 Luciferase assay
2.7 Semi-quantitative reverse transcriptase PCR and real-time PCR
2.8 RNA interference
2.9 Apoptosis assay
2.10 Statistics
3 Results
3.1 Gfi1 is repressed by p53 and inhibits apoptosis induced by DNA damage through upregulating Bcl-xL expression.
3.1.1 p53 inhibits the expression of GFI1 protein and mRNA
3.1.2 p53 represses GFI1 transcription through direct binding to its promoter
3.1.3 The GFI1 core promoter contains a p53 response element (RE)
3.1.4 Repression of GFI1 by p53 is not dependent on class I, II histone deacetylases (HDACs), p21Cip1 and E2F1
3.1.5 Gfi1 inhibits DNA damage induced apoptosis in a p53-independent manner
3.1.6 Gfi1 upregulates Bcl-xL, but does not affect Bax, Bak and Bcl-2 expression.
3.1.7 Bcl-xL is partially responsible for Gfi1 inhibition of DNA damage induced apoptosis.
3.2 Gfi1 upregulates c-Myc expression and inhibits c-Myc overexpression induced apoptosis
3.2.1 Overexpression of Gfi1 upregulates Myc protein and mRNA expression.
3.2.2 Gfi1 knockdown or deficiency leads to downregulation of Myc protein and mRNA expression.
3.2.3 Gfi1 overexpression inhibits Myc induced apoptosis.
3.2.4 Gfi1 abolishes Myc-mediated downregulation of Bcl-xL.
4 Discussion
4.1 Gfi1 is repressed by p53 through direct DNA binding
4.2 Biological significance of Gfi1 repression of p53
4.3 Gfi1 inhibits DNA damage induced apoptosis independent of p53
4.4 Gfi1 cooperates with c-Myc in lymphomagenesis by upregulating c-Myc expression and inhibiting c-Myc overexpression induced apoptosis.
4.5 Gfi1 upregulates Bcl-xL expression to inhibit apoptosis induced by DNA damage and Myc overexpression.
5 Future Directions
References
Appendix A List of Cell Lines Bài viết liên quan
