The central problems addressed in the proposed research are how the centrosome is organized, how it duplicates once per cell cycle, and how we go from the "parts list" for the organelle to a more complete understanding of how it works. The centrosome nucleates microtubules and helps to organize those microtubules to create useful arrays, including the mitotic spindle and the cilium. Work from my lab and others over the last 20 years at Stanford has identified molecules involved in microtubule nucleation, the central regulators of centrosome duplication, important structural proteins involved in duplication, and control mechanisms that govern centrosome number and link the centrosome and the cilium. Interest in the centrosome is strong because of the correlation between centrosome abnormalities and the development of cancer, and because of the role of the centrosome in ciliopathies, diseases related to primary cilium function, and microcephaly, a defect in neuronal development. The proposed experiments make use of the strengths that we have developed in reagents and assays for studying centrosome structure, function and duplication in different experimental systems. We have chosen to focus on the process in animal cells, tissues and extracts as they are the systems most relevant to our desire to understand the human centrosome in normal cell division, and in disease.
Three specific aims are addressed in this proposal:
Specific Aim 1 - Identify and characterize the interactions that define the centriole "origin of duplication" Specific Aim 2 - Characterize the mode of action of Mdm1, a unique negative regulator of centriole duplication.
Specific Aim 3 - Create centriole-less mammalian cells to address the function of the centrosome in the cell cycle, cell signaling, and nuclear functions.

Public Health Relevance

The centrosome is a component of the cell that sits at the center of a network of fibers, microtubules that perform work within the cell and receive and respond to signals. The centrosome is present in exactly one copy per cell and it duplicates every cell cycle, along with the chromosomes. Defects in the centrosome are associated with cancer, and developmental disorders including defects in brain development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM052022-18A1
Application #
8696153
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
1995-08-01
Project End
2018-02-28
Budget Start
2014-06-04
Budget End
2015-02-28
Support Year
18
Fiscal Year
2014
Total Cost
$454,987
Indirect Cost
$172,341
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Van de Mark, Daniel; Kong, Dong; Loncarek, Jadranka et al. (2015) MDM1 is a microtubule-binding protein that negatively regulates centriole duplication. Mol Biol Cell 26:3788-802
Firat-Karalar, Elif Nur; Stearns, Tim (2015) Probing mammalian centrosome structure using BioID proximity-dependent biotinylation. Methods Cell Biol 129:153-70
Vladar, Eszter K; Lee, Yin Loon; Stearns, Tim et al. (2015) Observing planar cell polarity in multiciliated mouse airway epithelial cells. Methods Cell Biol 127:37-54
Turk, Erin; Wills, Airon A; Kwon, Taejoon et al. (2015) Zeta-Tubulin Is a Member of a Conserved Tubulin Module and Is a Component of the Centriolar Basal Foot in Multiciliated Cells. Curr Biol 25:2177-83
Firat-Karalar, Elif Nur; Rauniyar, Navin; Yates 3rd, John R et al. (2014) Proximity interactions among centrosome components identify regulators of centriole duplication. Curr Biol 24:664-70
Lee, Joanna Y; Hong, Wan-Jen; Majeti, Ravindra et al. (2014) Centrosome-kinase fusions promote oncogenic signaling and disrupt centrosome function in myeloproliferative neoplasms. PLoS One 9:e92641
Fırat-Karalar, Elif Nur; Stearns, Tim (2014) The centriole duplication cycle. Philos Trans R Soc Lond B Biol Sci 369:
Lee, Yin Loon; Santé, Joshua; Comerci, Colin J et al. (2014) Cby1 promotes Ahi1 recruitment to a ring-shaped domain at the centriole-cilium interface and facilitates proper cilium formation and function. Mol Biol Cell 25:2919-33
Stearns, Tim (2014) Journey to the center of the centrosome. Dev Cell 28:603-4
Firat-Karalar, Elif N; Sante, Joshua; Elliott, Sarah et al. (2014) Proteomic analysis of mammalian sperm cells identifies new components of the centrosome. J Cell Sci 127:4128-33

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