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The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation
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Title
The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation
Name
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Wang
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Guannan
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Guannan Wang
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author
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Jin
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Shengkan
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Advisory Committee
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Shengkan Victor Jin
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chair
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Suh
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Nanjoo
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Advisory Committee
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Nanjoo Suh
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Liu
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Fang
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Advisory Committee
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Fang Liu
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Reiss
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Michael
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Advisory Committee
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Michael Reiss
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outside member
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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theses
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2008
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2008-05
Language
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English
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electronic
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xiv, 204 pages
Abstract
TGF-β regulates cell proliferation, differentiation, apoptosis, and extracellular matrix production. Smad proteins are central mediators of TGF-β signaling. Upon ligand binding, Smad2 and Smad3 are phosphorylated by the receptor at the C-terminal SxS motif. The phosphorylation triggers heteromeric complex formation with Smad4 and the translocation of the Smads into the nucleus, where they recruit co-activators, co-repressors and other transcription factors to activate or repress transcription of target genes.
The Smad3 linker region, a motif of 90 amino acid residues located between the N-terminal and C-terminal domains of Smad3, contains several serine/threonine-proline motifs, which are putative phosphorylation sites for proline-directed protein kinases such as Mitogen-Activated Protein Kinase (MAPK) family members and cyclin-dependent kinases (CDKs). We have shown that the Extracellular-signal Regulated Kinase (ERK) MAPK phosphorylates three linker sites Thr 179, Ser 204, and Ser 208 of Smad3, and that G1 CDKs phosphorylate Thr 179 and Ser 213 in the linker region and Thr 8 in the N-terminal domain of Smad3. Phosphorylation of Smad3 by CDK and ERK inhibits its transcriptional activity. In addition, TGF-β induces Smad3 phosphorylation on Thr 179, Ser 204, and Ser 208 in a C-tail phosphorylation-dependent manner, and the phosphorylation appears to be inhibitory. We have found that the linker region of Smad3 contains a transcriptional activation domain. Previous studies showed that the C-terminal domain of Smad3 is essential for Smad transcriptional activation through its interaction with the co-activator p300. We found that the Smad3 linker region can also interact with the co-activator p300. Deletion of the Smad3 linker region from the full-length protein abolished the ability of Smad3 to activate several TGF-β responsive reporter genes. We further showed that the linker region and the C-terminal domain of Smad3 synergize for transcriptional activation in the presence of TGF-β. In addition, mutation of the CDK and ERK phosphorylation sites in Smad3 increases its ability to interact with p300. This suggests that CDK and ERK phosphorylation of Smad3 inhibits its binding to p300. Since cancer cells often contain high levels of CDK and ERK activity, CDK and ERK phosphorylation of Smad3 may contribute to tumorigenesis and TGF-β resistance in cancers.
The Smad3 linker region, a motif of 90 amino acid residues located between the N-terminal and C-terminal domains of Smad3, contains several serine/threonine-proline motifs, which are putative phosphorylation sites for proline-directed protein kinases such as Mitogen-Activated Protein Kinase (MAPK) family members and cyclin-dependent kinases (CDKs). We have shown that the Extracellular-signal Regulated Kinase (ERK) MAPK phosphorylates three linker sites Thr 179, Ser 204, and Ser 208 of Smad3, and that G1 CDKs phosphorylate Thr 179 and Ser 213 in the linker region and Thr 8 in the N-terminal domain of Smad3. Phosphorylation of Smad3 by CDK and ERK inhibits its transcriptional activity. In addition, TGF-β induces Smad3 phosphorylation on Thr 179, Ser 204, and Ser 208 in a C-tail phosphorylation-dependent manner, and the phosphorylation appears to be inhibitory. We have found that the linker region of Smad3 contains a transcriptional activation domain. Previous studies showed that the C-terminal domain of Smad3 is essential for Smad transcriptional activation through its interaction with the co-activator p300. We found that the Smad3 linker region can also interact with the co-activator p300. Deletion of the Smad3 linker region from the full-length protein abolished the ability of Smad3 to activate several TGF-β responsive reporter genes. We further showed that the linker region and the C-terminal domain of Smad3 synergize for transcriptional activation in the presence of TGF-β. In addition, mutation of the CDK and ERK phosphorylation sites in Smad3 increases its ability to interact with p300. This suggests that CDK and ERK phosphorylation of Smad3 inhibits its binding to p300. Since cancer cells often contain high levels of CDK and ERK activity, CDK and ERK phosphorylation of Smad3 may contribute to tumorigenesis and TGF-β resistance in cancers.
Note
(type = degree)
Ph.D.
Note
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Includes bibliographical references (p. 191-203).
Subject
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Topic
Biochemistry
Subject
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Topic
Smad proteins
Subject
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Topic
Transforming growth factors-beta
Subject
(ID = SUBJ4);
(authority = ETD-LCSH)
Topic
Cellular signal transduction
Subject
(ID = SUBJ5);
(authority = ETD-LCSH)
Topic
Cancer cells--Growth--Regulation
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17061
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doi:10.7282/T3V1256Q
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ETD doctoral
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Open
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Guannan WANG
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Rutgers University. Graduate School - New Brunswick
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Non-exclusive ETD 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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