The purpose of this proposal is to understand the role of zipcode-binding protein ZBP1 in the mechanism of mRNA localization. Over the last project period, we have identified and characterized the role of this protein in localizing ?-actin mRNA to the periphery of cells where it is involved in synthesizing proteins important for neuronal growth and cell motility. This protein binds to the """"""""zipcode"""""""" of mRNA and transduces nucleic acid sequences into cellular spatial information. Surprisingly, this protein is at a central point in the cellular basis of disease, we have found it to be a metastasis suppressor and play a role in neuronal pathology and even in behavior. We hypothesize that ZBP1 is carrying a group of mRNAs to focal adhesion complexes or sites of cell-cell contact and this regulates intercellular or cell-substrate interactions. Our experimental focus in this work is to identify the RNA and protein binding partners of ZBP1;in particular using TIRF. We will then characterize its crystal structure and determine how it interacts with specific proteins to move mRNAs and allow their expression. Finally, we will visualize these processes in living cells from mice carrying a modified ?-actin mRNA and in a knock-out of ZBP1.

Public Health Relevance

We have discovered a protein that controls how and where other proteins are made in the cell. We have found that this protein is implicated in suppressing cancer metastasis and maintaining normal nerve function. We are investigating how this protein works to localize protein synthesis in specific regions of the cell by using a super-sensitive microscope to watch the process occur in living cells and tissues from genetically engineered mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084364-17
Application #
7898578
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Deatherage, James F
Project Start
1992-03-03
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
17
Fiscal Year
2010
Total Cost
$386,199
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Wang, Guangli; Huang, Zhenqiang; Liu, Xin et al. (2016) IMP1 suppresses breast tumor growth and metastasis through the regulation of its target mRNAs. Oncotarget 7:15690-702
Song, Tingting; Zheng, Yi; Wang, Yarong et al. (2015) Specific interaction of KIF11 with ZBP1 regulates the transport of ?-actin mRNA and cell motility. J Cell Sci 128:1001-10
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Buxbaum, Adina R; Wu, Bin; Singer, Robert H (2014) Single ?-actin mRNA detection in neurons reveals a mechanism for regulating its translatability. Science 343:419-22
Wu, Bin; Chen, Jiahao; Singer, Robert H (2014) Background free imaging of single mRNAs in live cells using split fluorescent proteins. Sci Rep 4:3615
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