Abstract/Details

Regulation of immunobiology and skeletal biology by the zinc finger adaptor protein Schnurri-3


2007 2007

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Abstract (summary)

Mechanisms governing cell type-specific regulation of gene expression in the immune and skeletal systems are poorly-understood. We identified Schnurri-3 (Shn3), a large zinc finger-containing nuclear protein based on its regulated pattern of expression in the immune system. Using overexpression and loss-of-function analyses, we determined that Shn3 plays an important role in regulating the production of the cytokine interleukin-2 (IL-2) by T lymphocytes. We determined that Shn3 regulates IL-2 expression by activating the IL-2 gene promoter through AP-1 transcription factor binding sites.

We also noted that mice lacking Shn3 show dramatic accrual of postnatal bone mass. We determined that Shn3 inhibits bone formation by osteoblasts. Using overexpression and loss-of-function analyses, we determined that Shn3 regulates the activity of Runx2, a transcription factor critical in determining osteoblast differentiation and function. Shn3 regulates Runx2 by controlling its stability. Shn3 accomplishes this effect by recruiting the E3 ubiquitin ligase WWP1 to Runx2. We used RNAi to reduce levels of WWP1 in osteoblasts, and noted that WWP1 RNAi osteoblasts resemble, to a large degree, Shn3-deficient cells.

We also asked whether Shn3/WWP1 might target regulatory molecules other than Runx2 in osteoblasts. Using a candidate gene approach, we determined that Shn3/WWP1 also regulate levels and activity of the kinase RSK2. RSK2 controls extracellular matrix production by mature osteoblasts, and Shn3-deficient cells have increased levels of RSK2 activity. Reducing RSK2 levels or activity caused Shn3-deficient osteoblasts to produce less extracellular matrix components. Therefore, Shn3/WWPI target both Runx2 and RSK2 to inhibit osteoblast function. Future studies will be required to determine if additional substrates exist.

Finally, we asked whether decreased osteoclast activity might contribute to the increased bone mass in Shn3-deficient animals. Although Shn3 plays no role in osteoclast development, Shn3-deficient osteoblasts cannot fully drive osteoclast differentiation in vitro. Shn3-deficient osteoblasts produce less of the osteoclastogenic cytokine RANKL and more of the anti-osteoclastogenic factor OPG. Therefore, Shn3-deficient mice display a dramatic high bone mass phenotype to due increased bone formation by osteoblasts and reduced bone resorption by osteoclasts.

Indexing (details)


Subject
Molecular biology;
Immunology
Classification
0307: Molecular biology
0982: Immunology
Identifier / keyword
Health and environmental sciences; Biological sciences; Immunobiology; Osteoblasts; Schnurri-3; Skeletal biology; Ubiquitin ligase; Zinc finger proteins
Title
Regulation of immunobiology and skeletal biology by the zinc finger adaptor protein Schnurri-3
Author
Wein, Marc Nathan
Number of pages
125
Publication year
2007
Degree date
2007
School code
0084
Source
DAI-B 68/10, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549280071
Advisor
Glimcher, Laurie H.
University/institution
Harvard University
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3285566
ProQuest document ID
304849070
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304849070
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