Award Date

12-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Committee Member

Ronald K. Gary

Second Committee Member

Bryan L. Spangelo

Third Committee Member

Ernesto Abel-Santos

Fourth Committee Member

Dong-Chan Lee

Fifth Committee Member

Frank van Breukelen

Number of Pages

134

Abstract

Cancer cells evade senescence, apoptosis, and other constraints on proliferation, often via mutation of the p53 tumor suppressor gene (TP53). Normal human lung fibroblasts have been shown to enter premature senescence upon exposure to beryllium. In these cells, BeSO4 stabilizes p53 protein, increases p21 gene expression, induces senescence-associated β-galactosidase activity and causes cell proliferation arrest. In the present study, we have investigated whether BeSO4 is able to induce similar effects in cancer cells that have wildtype p53. We have demonstrated that beryllium salt at low concentration can induce molecular changes in the p53 signaling pathway leading to cell cycle arrest in beryllium-sensitive cancer cells. The p53 transcription factor is the central regulator of the mammalian DNA damage response. However, unlike most agents that activate p53, beryllium did not cause DNA damage. We have discovered that the growth arresting effects of beryllium are mediated through the p53-dependent p21 pathway. We have also found that BeSO4 may be influencing the regulation of cyclin E2, a cyclin that controls passage of cells from G1 to S phase of the cell cycle. Increased caspase 3/7 activity was also seen in response to BeSO4 treatment. However, the number of cells undergoing apoptosis was not proportional to the activity of caspase 3/7, suggesting that the beryllium response is primarily cytostatic rather than apoptotic. These observations indicate that beryllium suppresses cell proliferation through a senescence-related p53 signaling pathway that differs from the DNA damage response pathway. These unusual properties make beryllium salt a potent tool to investigate p53-mediated growth control pathways in both normal and cancerous cell types.

Keywords

A172; Beryllium; Cancer cells – Growth – Regulation; Caspase 3; Cell signaling; Cells – Growth; Cyclin E; DNA damage; Genetics; Life cycles (Biology); P21; P53

Disciplines

Biochemistry | Medical Genetics | Molecular Biology | Oncology

Language

English


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