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You searched for +publisher:"Rutgers University" +contributor:("Wang, Guannan"). One record found.

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Rutgers University

1. Wang, Guannan. The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation.

Degree: PhD, Biochemistry, 2008, Rutgers University

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.

Advisors/Committee Members: Wang, Guannan (author), Jin, Shengkan (chair), Suh, Nanjoo (internal member), Liu, Fang (internal member), Reiss, Michael (outside member).

Subjects/Keywords: Smad proteins; Transforming growth factors-beta; Cellular signal transduction; Cancer cells – Growth – Regulation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Wang, G. (2008). The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation. (Doctoral Dissertation). Rutgers University. Retrieved from http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17061

Chicago Manual of Style (16th Edition):

Wang, Guannan. “The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation.” 2008. Doctoral Dissertation, Rutgers University. Accessed May 09, 2021. http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17061.

MLA Handbook (7th Edition):

Wang, Guannan. “The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation.” 2008. Web. 09 May 2021.

Vancouver:

Wang G. The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation. [Internet] [Doctoral dissertation]. Rutgers University; 2008. [cited 2021 May 09]. Available from: http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17061.

Council of Science Editors:

Wang G. The Smad3 linker region: transcriptional activity and phosphorylation-mediated regulation. [Doctoral Dissertation]. Rutgers University; 2008. Available from: http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17061

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