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Arsenic modulates key signaling path...

University of California, Davis.

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Arsenic modulates key signaling pathways to disrupt keratinocyte fate.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Arsenic modulates key signaling pathways to disrupt keratinocyte fate./
Author:	Reznikova, Tatiana V.
Description:	122 p.
Notes:	Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0983.
Contained By:	Dissertation Abstracts International69-02B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3303193
ISBN:	9780549493495

Arsenic modulates key signaling pathways to disrupt keratinocyte fate.
Reznikova, Tatiana V.

Arsenic modulates key signaling pathways to disrupt keratinocyte fate. - 122 p.

Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0983.

Thesis (Ph.D.)--University of California, Davis, 2007.

Chronic exposure to arsenic in contaminated drinking water may result in skin disorders, including skin cancer. An animal model where arsenite treatment alone causes carcinogenesis has been elusive, complicating the process of studying arsenic. We demonstrate that low micromolar concentrations of arsenite in culture lead to preservation of keratinocyte proliferative potential as measured by colony forming efficiency (CFE) and rapidly adhering colony-forming cells (RACs). Further, arsenite treatment suppresses terminal differentiation and prevents the increase in cell size observed as keratinocytes differentiate. Using CFE, cell size and differentiation as endpoints, we examined signaling pathways targeted by arsenite to better understand how arsenic causes cancer. Arsenite opposes the negative action of insulin, which promotes exit from the germinative pool into terminal differentiation. Central to this process is the EGFR, as inhibiting EGFR activity reversed the effect of arsenite on all endpoints measured. However, insulin signaling also regulates an EGFR-independent pathway to promote differentiation since EGFR inhibition reversed the effects of insulin on CFE, but failed to overcome the effects on cell size and differentiation. We establish the PI3-kinase/mTOR pathway as the downstream transducer of insulin signaling responsible for regulating proliferative potential. Further, this insulin pathway and the EGFR function in parallel since addition of the PI3-kinase inhibitor LY294002 or the mTOR inhibitor rapamycin to arsenite treated cultures resulted in additive effects on CFE, cell size and suppression of differentiation. PKCdelta appears to be the converging point of the insulin and EGFR pathways and is responsible for integrating these signals to regulate proliferative potential. Also downstream of the EGFR is Notch-1, which is responsible for regulating keratinocyte fate determination. Arsenite suppresses Notch-1 signaling by interfering with its cleavage by gamma-secretase in an EGFR-dependent manner. We conclude that arsenic may be acting as a co-carcinogen by shifting the balance to preserve the population of cells with the highest proliferative potential. Over time this may lead to the expansion of cells with altered genomes that would normally be eliminated by differentiation. Thus, elucidating the signaling pathways disrupted by arsenite that regulate proliferative potential greatly advances our understanding of how arsenic causes cancer.

ISBN: 9780549493495Subjects--Topical Terms:

1017719
Biology, Molecular.

Arsenic modulates key signaling pathways to disrupt keratinocyte fate.
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520 $a Chronic exposure to arsenic in contaminated drinking water may result in skin disorders, including skin cancer. An animal model where arsenite treatment alone causes carcinogenesis has been elusive, complicating the process of studying arsenic. We demonstrate that low micromolar concentrations of arsenite in culture lead to preservation of keratinocyte proliferative potential as measured by colony forming efficiency (CFE) and rapidly adhering colony-forming cells (RACs). Further, arsenite treatment suppresses terminal differentiation and prevents the increase in cell size observed as keratinocytes differentiate. Using CFE, cell size and differentiation as endpoints, we examined signaling pathways targeted by arsenite to better understand how arsenic causes cancer. Arsenite opposes the negative action of insulin, which promotes exit from the germinative pool into terminal differentiation. Central to this process is the EGFR, as inhibiting EGFR activity reversed the effect of arsenite on all endpoints measured. However, insulin signaling also regulates an EGFR-independent pathway to promote differentiation since EGFR inhibition reversed the effects of insulin on CFE, but failed to overcome the effects on cell size and differentiation. We establish the PI3-kinase/mTOR pathway as the downstream transducer of insulin signaling responsible for regulating proliferative potential. Further, this insulin pathway and the EGFR function in parallel since addition of the PI3-kinase inhibitor LY294002 or the mTOR inhibitor rapamycin to arsenite treated cultures resulted in additive effects on CFE, cell size and suppression of differentiation. PKCdelta appears to be the converging point of the insulin and EGFR pathways and is responsible for integrating these signals to regulate proliferative potential. Also downstream of the EGFR is Notch-1, which is responsible for regulating keratinocyte fate determination. Arsenite suppresses Notch-1 signaling by interfering with its cleavage by gamma-secretase in an EGFR-dependent manner. We conclude that arsenic may be acting as a co-carcinogen by shifting the balance to preserve the population of cells with the highest proliferative potential. Over time this may lead to the expansion of cells with altered genomes that would normally be eliminated by differentiation. Thus, elucidating the signaling pathways disrupted by arsenite that regulate proliferative potential greatly advances our understanding of how arsenic causes cancer.
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