Abstract/Details

Molecular Aspects of Transforming Growth Factor <i>beta </i> (TGF-β) Resistance in Atherosclerosis: Role of Smad3 in Antiproliferative Response


2011 2011

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Abstract (summary)

The transforming growth factor type-β (TGF-β) family plays a major role in the repair of injured blood vessel walls and induces a wide range of responses in vascular smooth muscle cells (VSMCs). One very important function of TGF-β is its antiproliferative effect. Normal VSMCs generally exhibit reduced proliferation in response to TGF-β stimuli, while lesion-derived VSMCs (LDCs) show a selective resistance to the antiproliferative effect of TGF-β, as seen in atherosclerosis. The overall goal of this dissertation was to examine the mechanisms and factors that contribute to smooth muscle cells resistance to TGF-β signaling in atherosclerosis.

Among different causes of resistance, there were identified several molecular mechanisms that may be responsible for the TGF-β-induced antiproliferative response. Primarily, lesion-derived VSMC have a low level of Smad3 protein due to its rapid degradation by the ubiquitin-proteasomal machinery. Moreover, blocking the degradation of Smad3 is capable of restoring the adequate level of detectable endogenous Smad3 protein, but does not affect significantly the antiproliferative response, suggesting that non-degraded Smad3 may be sequestered in the cytoplasm and the translocation to the nucleus of phosphorylated protein is impeded. Overall, the general conclusion of this thesis is that an adequate level of Smad3 is necessary for the proper antiproliferative response in lesion-derived VSMCs, but by itself, the adequate level is not sufficient to create a significant antiproliferative response to TGF-β due to a possible sequestration of Smad3 in cytosol and an impaired shuttling of phosphorylated Smad3 into the nucleus. Most likely, the sequestration of Smad3 in cytoplasm is not the only, or main, reason for the lack of an antiproliferative response in resistant cells expressing Smad3.

Indexing (details)


Subject
Molecular biology;
Biochemistry;
Medicine
Classification
0307: Molecular biology
0487: Biochemistry
0564: Medicine
Identifier / keyword
Health and environmental sciences; Pure sciences; Biological sciences; Antiproliferative response; Atherosclerosis; Resistance; Smad3; Tgf beta
Title
Molecular Aspects of Transforming Growth Factor <i>beta </i> (TGF-β) Resistance in Atherosclerosis: Role of Smad3 in Antiproliferative Response
Author
Toma, Ian
Number of pages
161
Publication year
2011
Degree date
2011
School code
0075
Source
DAI-B 72/11, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124825274
Advisor
McCaffrey, Timothy A.
Committee member
Bukrinsky, Michael; Fu, Sidney; Goldstein, Allan L.; Rojkind, Marcos
University/institution
The George Washington University
Department
Biochemistry and Molecular Biology
University location
United States -- District of Columbia
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3468508
ProQuest document ID
898363895
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/898363895
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