東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

DNA damage-induced cell cycle checkp...

Kohn, Ethan Alfred.

FindBook

Google Book

Amazon

博客來

DNA damage-induced cell cycle checkpoints as a target for cancer therapy.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	DNA damage-induced cell cycle checkpoints as a target for cancer therapy./
作者:	Kohn, Ethan Alfred.
面頁冊數:	240 p.
附註:	Source: Dissertation Abstracts International, Volume: 65-01, Section: B, page: 0033.
Contained By:	Dissertation Abstracts International65-01B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3119580

DNA damage-induced cell cycle checkpoints as a target for cancer therapy.
Kohn, Ethan Alfred.

DNA damage-induced cell cycle checkpoints as a target for cancer therapy. - 240 p.

Source: Dissertation Abstracts International, Volume: 65-01, Section: B, page: 0033.

Thesis (Ph.D.)--Dartmouth College, 2004.

Cells respond to DNA damage by activating signal transduction pathways that cause cell cycle arrest at checkpoints in G1, S, or G 2 phases of the cell cycle; this allows time for repair of damaged DNA. The G1 checkpoint is dependent upon the function of the p53 tumor suppressor, whereas S and G2 checkpoints are activated independently of p53. Prior studies showed that p53-defective cells that arrest in S and G2, but not p53 wild-type cells, can be sensitized to DNA damage by the checkpoint inhibitor caffeine, which causes premature cell cycle progression and lethal mitosis. This laboratory previously demonstrated that UCN-01, an inhibitor of Chk1/2 activity, also abrogates G2 arrest and sensitizes p53-defective cells to DNA damage. The G2 checkpoint involves the inhibition of the Cdc25C phosphatase by the Chk1 and Chk2 kinases; however, the mechanism of the S phase checkpoint has remained unclear. Here, we examined the mechanism of S phase arrest induced by the topoisomerase I inhibitor SN38 in p53-defective breast cancer cells and p53 wild-type breast cells. It was found that Cdc25C is not the critical target of Chk1/2 in S phase; rather, the S phase checkpoint functions through the Chk1-Cdc25A-cyclin E/Cdk2 pathway. UCN-01 induced S and G2 progression in the p53-defective MDA-MB-231 cells at low nanomolar concentrations, whereas higher concentrations caused lethal mitosis without cell cycle progression, likely due to inhibition of C-TAK 1. Other novel, structurally related checkpoint inhibitors ICP-1 and Go6976 also abrogated arrest, but did not appear to inhibit C-TAK1. These analogs differ from UCN-01 in that their potency was not inhibited by human serum proteins. In p53 wild-type cells, S phase arrest was maintained in the presence of UCN-01, by p53-mediated transcriptional activation of target genes such as p21. G2 arrest was also maintained in p53 wild-type cells, by p53-mediated repression of genes such as cyclin B. These studies provide insight into the mechanism of the p53-independent S phase checkpoint, and the role of p53 in protecting cells against checkpoint inhibition. These results will facilitate the development of checkpoint inhibitors as anticancer drugs.Subjects--Topical Terms:

1017686
Biology, Cell.

DNA damage-induced cell cycle checkpoints as a target for cancer therapy.
LDR:03077nmm 2200277 4500 001 1861084
005 20041111103542.5
008 130614s2004 eng d
035 $a (UnM)AAI3119580
035 $a AAI3119580
040 $a UnM $c UnM
100 1 $a Kohn, Ethan Alfred. $3 1948701
245 1 0 $a DNA damage-induced cell cycle checkpoints as a target for cancer therapy.
300 $a 240 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-01, Section: B, page: 0033.
500 $a Chair: Alan Eastman.
502 $a Thesis (Ph.D.)--Dartmouth College, 2004.
520 $a Cells respond to DNA damage by activating signal transduction pathways that cause cell cycle arrest at checkpoints in G1, S, or G 2 phases of the cell cycle; this allows time for repair of damaged DNA. The G1 checkpoint is dependent upon the function of the p53 tumor suppressor, whereas S and G2 checkpoints are activated independently of p53. Prior studies showed that p53-defective cells that arrest in S and G2, but not p53 wild-type cells, can be sensitized to DNA damage by the checkpoint inhibitor caffeine, which causes premature cell cycle progression and lethal mitosis. This laboratory previously demonstrated that UCN-01, an inhibitor of Chk1/2 activity, also abrogates G2 arrest and sensitizes p53-defective cells to DNA damage. The G2 checkpoint involves the inhibition of the Cdc25C phosphatase by the Chk1 and Chk2 kinases; however, the mechanism of the S phase checkpoint has remained unclear. Here, we examined the mechanism of S phase arrest induced by the topoisomerase I inhibitor SN38 in p53-defective breast cancer cells and p53 wild-type breast cells. It was found that Cdc25C is not the critical target of Chk1/2 in S phase; rather, the S phase checkpoint functions through the Chk1-Cdc25A-cyclin E/Cdk2 pathway. UCN-01 induced S and G2 progression in the p53-defective MDA-MB-231 cells at low nanomolar concentrations, whereas higher concentrations caused lethal mitosis without cell cycle progression, likely due to inhibition of C-TAK 1. Other novel, structurally related checkpoint inhibitors ICP-1 and Go6976 also abrogated arrest, but did not appear to inhibit C-TAK1. These analogs differ from UCN-01 in that their potency was not inhibited by human serum proteins. In p53 wild-type cells, S phase arrest was maintained in the presence of UCN-01, by p53-mediated transcriptional activation of target genes such as p21. G2 arrest was also maintained in p53 wild-type cells, by p53-mediated repression of genes such as cyclin B. These studies provide insight into the mechanism of the p53-independent S phase checkpoint, and the role of p53 in protecting cells against checkpoint inhibition. These results will facilitate the development of checkpoint inhibitors as anticancer drugs.
590 $a School code: 0059.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Health Sciences, Oncology. $3 1018566
650 4 $a Health Sciences, Toxicology. $3 1017752
690 $a 0379
690 $a 0992
690 $a 0383
710 2 0 $a Dartmouth College. $3 1025074
773 0 $t Dissertation Abstracts International $g 65-01B.
790 1 0 $a Eastman, Alan, $e advisor
790 $a 0059
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3119580