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Cellular and biochemical regulation of Cdc25A phosphatase by nitrosative stress.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Cellular and biochemical regulation of Cdc25A phosphatase by nitrosative stress./
Author:	Tomko, Robert J. Jr.
Description:	166 p.
Notes:	Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6728.
Contained By:	Dissertation Abstracts International69-11B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3335840
ISBN:	9780549896401

Cellular and biochemical regulation of Cdc25A phosphatase by nitrosative stress.
Tomko, Robert J. Jr.

Cellular and biochemical regulation of Cdc25A phosphatase by nitrosative stress. - 166 p.

Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6728.

Thesis (Ph.D.)--University of Pittsburgh, 2008.

Numerous reports correlate nitric oxide (·NO) production with stalled S-phase progression, but the molecular mechanism(s) of cell cycle arrest remains elusive. Paradoxically numerous human tumors are exposed to vast quantities of nitric oxide and its reactive byproducts in situ , yet they continue to grow and proliferate. The dual-specificity phosphatase Cdc25A promotes cell cycle progression by dephosphorylating and activating cyclin-dependent kinases. Deregulation of Cdc25A is characteristic of human tumors, accelerates the cell cycle, and confers resistance to apoptosis, highlighting the importance of stringent Cdc25A control. Biochemical and structural analyses of Cdc25A indicate the potential for inhibition by S-nitrosation of the catalytic cysteine, providing a linkage between ·NO and cytostatic signaling. Thus, the overall hypothesis examined in this dissertation was that Cdc25A is a target and transducer of signaling by ·NO and ·NO-derived reactive species. The specific aims were to: (1) probe the susceptibility of Cdc25A to enzymatic regulation by ·NO-derived reactive species; (2) examine regulation of Cdc25A protein in nitrosatively challenged cells; and (3) determine whether Cdc25A activity was limiting for S-phase progression in nitrosatively-challenged tumor cells. My studies identified novel mechanisms controlling Cdc25A abundance and activity. S-Nitrosothiols rapidly S-nitrosated and inactivated Cdc25A in vitro , and Cdc25A activity was restored by reductants. Generation of nitrosative stress in cells either by iNOS-derived ·NO or the cell-permeable S-nitrosating agent S-nitrosocysteine ethyl ester (SNCEE) caused translational inhibition of Cdc25A via hyperphosphorylation and inhibition of the eukaryotic translational regulator eIF2alpha. Although iNOS-derived ·NO and SNCEE inhibited DNA synthesis coincident with Cdc25A loss, restoration of Cdc25A activity in nitrosatively-challenged cells did not alter DNA synthesis inhibition, distinguishing nitrosative inhibition of DNA synthesis from the canonical intra-S-phase checkpoint. SNCEE decoupled Cdc25A from ASK-1 and sensitized cells to chemotherapeutic-induced apoptosis, suggesting that Cdc25A suppression by nitrosative stress may lower the apoptotic threshold in nitrosatively-challenged cells by priming ASK-1 for activation. In summary, these studies describe novel regulation of Cdc25A translation and activity, and a model wherein selective inhibition of Cdc25A phosphatase-dependent and independent activities can occur under nitrosative stress, and implicate Cdc25A as a regulator of apoptotic threshold following nitrosative insult via priming of ASK-1.

ISBN: 9780549896401Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Cellular and biochemical regulation of Cdc25A phosphatase by nitrosative stress.
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100 1 $a Tomko, Robert J. Jr. $3 1021802
245 1 0 $a Cellular and biochemical regulation of Cdc25A phosphatase by nitrosative stress.
300 $a 166 p.
500 $a Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6728.
502 $a Thesis (Ph.D.)--University of Pittsburgh, 2008.
520 $a Numerous reports correlate nitric oxide (·NO) production with stalled S-phase progression, but the molecular mechanism(s) of cell cycle arrest remains elusive. Paradoxically numerous human tumors are exposed to vast quantities of nitric oxide and its reactive byproducts in situ , yet they continue to grow and proliferate. The dual-specificity phosphatase Cdc25A promotes cell cycle progression by dephosphorylating and activating cyclin-dependent kinases. Deregulation of Cdc25A is characteristic of human tumors, accelerates the cell cycle, and confers resistance to apoptosis, highlighting the importance of stringent Cdc25A control. Biochemical and structural analyses of Cdc25A indicate the potential for inhibition by S-nitrosation of the catalytic cysteine, providing a linkage between ·NO and cytostatic signaling. Thus, the overall hypothesis examined in this dissertation was that Cdc25A is a target and transducer of signaling by ·NO and ·NO-derived reactive species. The specific aims were to: (1) probe the susceptibility of Cdc25A to enzymatic regulation by ·NO-derived reactive species; (2) examine regulation of Cdc25A protein in nitrosatively challenged cells; and (3) determine whether Cdc25A activity was limiting for S-phase progression in nitrosatively-challenged tumor cells. My studies identified novel mechanisms controlling Cdc25A abundance and activity. S-Nitrosothiols rapidly S-nitrosated and inactivated Cdc25A in vitro , and Cdc25A activity was restored by reductants. Generation of nitrosative stress in cells either by iNOS-derived ·NO or the cell-permeable S-nitrosating agent S-nitrosocysteine ethyl ester (SNCEE) caused translational inhibition of Cdc25A via hyperphosphorylation and inhibition of the eukaryotic translational regulator eIF2alpha. Although iNOS-derived ·NO and SNCEE inhibited DNA synthesis coincident with Cdc25A loss, restoration of Cdc25A activity in nitrosatively-challenged cells did not alter DNA synthesis inhibition, distinguishing nitrosative inhibition of DNA synthesis from the canonical intra-S-phase checkpoint. SNCEE decoupled Cdc25A from ASK-1 and sensitized cells to chemotherapeutic-induced apoptosis, suggesting that Cdc25A suppression by nitrosative stress may lower the apoptotic threshold in nitrosatively-challenged cells by priming ASK-1 for activation. In summary, these studies describe novel regulation of Cdc25A translation and activity, and a model wherein selective inhibition of Cdc25A phosphatase-dependent and independent activities can occur under nitrosative stress, and implicate Cdc25A as a regulator of apoptotic threshold following nitrosative insult via priming of ASK-1.
590 $a School code: 0178.
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
710 2 $a University of Pittsburgh. $3 958527
773 0 $t Dissertation Abstracts International $g 69-11B.
790 $a 0178
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3335840