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Molecular regulation of insulin-like growth factor binding protein-5 by signaling molecules downstream of the IGF-I receptor in mammary epithelial cells
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TitleInfo
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Title
Molecular regulation of insulin-like growth factor binding protein-5 by signaling molecules downstream of the IGF-I receptor in mammary epithelial cells
SubTitle
PartName
PartNumber
NonSort
Identifier
ETD_1397
Identifier
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000050495
Language
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eng
Genre
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theses
Subject
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(authority = RUETD)
Topic
Microbiology and Molecular Genetics
Subject
(ID = SBJ-2);
(authority = ETD-LCSH)
Topic
Insulin-like growth factor-binding proteins
Subject
(ID = SBJ-3);
(authority = ETD-LCSH)
Topic
Mammary glands
Abstract
The insulin-like growth factor binding proteins (IGFBP) are important regulators of mammary epithelial cell (MEC) growth and can either enhance or inhibit IGF-I action. IGF-I activates the IGF-I receptor (IGF-IR) to initiate two well-characterized signaling pathways; the phosphoinositide 3-kinase pathway (PI3K) and the mitogen activated protein kinase (MAPK) pathway. In the bovine MEC line MAC-T, the PI3K pathway is required for both basal and IGF-I stimulated IGFBP-5 expression. In contrast, inhibition of the MAPK pathway with the chemical inhibitor PD98059 leads to an increase in IGFBP-5 expression in both basal and IGF-I treated conditions. In the present study, we identified molecules downstream of the IGF-IR that might play a role in the inhibitory regulation of IGFBP-5 expression via the MAPK pathway.
The MAPK pathway terminates with the activation of ERK1/2. Activated ERK1/2 enters the nucleus where it affects numerous transcriptional factors. ERK1/2 has been shown to inhibit activation of the peroxisome proliferator-activated receptor gamma (PPARγ). Inhibition of PPARγ with the chemical inhibitor GW9662 led to a decrease in IGFBP-5 message in PD98059-treated MAC-T. Activation of PPARγ and PPARβ/δ via the agonists Rosiglitazone and GW0742, respectively, was found to increase basal IGFBP-5 mRNA expression in murine MEC but not in MAC-T cells.
While PPARγ contributed to the PD98059-stimulated increase in IGFBP-5 message, it was unable to account for the total increase. We therefore examined the promoter region of IGFBP-5 to identify factors that could be affected by mitogens. Both mouse and human IGFBP-5 promoters contain a consensus NFκB binding site. In the present study, phenethyl caffeiate, an inhibitor of NFκB, almost completely inhibited the increase in IGFBP-5 observed with PD98059 and IGF-I + PD98059-stimulated IGFBP-5 mRNA and protein expression in MAC-T cells. Interestingly, IGFBP-3 expression was inversely regulated by phenethyl caffeiate.
In conclusion the synergistic increase in IGFBP-5 expression observed with IGF-I and inhibition of the MAPK pathway may be due to the formation of a PPARγ NFκB complex that binds to the promoter region of IGFBP-5. Rapid ERK dephosphorylation has been reported in involution, therefore this regulation may be important in inducing IGFBP-5 during involution in the bovine mammary gland.
The MAPK pathway terminates with the activation of ERK1/2. Activated ERK1/2 enters the nucleus where it affects numerous transcriptional factors. ERK1/2 has been shown to inhibit activation of the peroxisome proliferator-activated receptor gamma (PPARγ). Inhibition of PPARγ with the chemical inhibitor GW9662 led to a decrease in IGFBP-5 message in PD98059-treated MAC-T. Activation of PPARγ and PPARβ/δ via the agonists Rosiglitazone and GW0742, respectively, was found to increase basal IGFBP-5 mRNA expression in murine MEC but not in MAC-T cells.
While PPARγ contributed to the PD98059-stimulated increase in IGFBP-5 message, it was unable to account for the total increase. We therefore examined the promoter region of IGFBP-5 to identify factors that could be affected by mitogens. Both mouse and human IGFBP-5 promoters contain a consensus NFκB binding site. In the present study, phenethyl caffeiate, an inhibitor of NFκB, almost completely inhibited the increase in IGFBP-5 observed with PD98059 and IGF-I + PD98059-stimulated IGFBP-5 mRNA and protein expression in MAC-T cells. Interestingly, IGFBP-3 expression was inversely regulated by phenethyl caffeiate.
In conclusion the synergistic increase in IGFBP-5 expression observed with IGF-I and inhibition of the MAPK pathway may be due to the formation of a PPARγ NFκB complex that binds to the promoter region of IGFBP-5. Rapid ERK dephosphorylation has been reported in involution, therefore this regulation may be important in inducing IGFBP-5 during involution in the bovine mammary gland.
PhysicalDescription
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electronic resource
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vii, 61 p. : ill.
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M.S.
Note
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Includes bibliographical references (p. 51-61)
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Brandimarto
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Jeffrey Alan
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Jeffrey Alan Brandimarto
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Cohick
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Wendie
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chair
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Advisory Committee
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Wendie S Cohick
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Denhardt
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David
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internal member
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Advisory Committee
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David Denhardt
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Axelrod
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David
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internal member
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Advisory Committee
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David Axelrod
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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school
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2009
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2009-01
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xx
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NjNbRU
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Rutgers University Electronic Theses and Dissertations
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ETD
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
Identifier
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doi:10.7282/T32J6C4V
Genre
(authority = ExL-Esploro)
ETD graduate
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The author owns the copyright to this work.
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Open
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Non-exclusive ETD license
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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