Areas of Interest
Microtubules are one of the major organizing structures in the
cell. They give cells their shape, help them move, and serve as
tracks for transport of organelles towards or away from the
nucleus. During cell division, microtubules form the mitotic
spindle, responsible for accurate chromosome segregation.
Abnormalities of microtubule organization can lead to the
aberrant mitoses that are a major hallmark of cancer. Aneuploidy
resulting from microtubule defects is also an important cause of
infertility. Several potent drugs that disrupt microtubules are
used clinically -- Taxol is a well known example. These drugs
are extremely effective in blocking mitosis, in cancer cells, as
well as in disorders of cell proliferation such as autoimmune
disease and coronary artery hypertrophy after stent placement.
What we need now is a better understanding of the mechanisms of
microtubule disruption in cancer, and better drugs that are more
specific for mitotic microtubules.
My lab studies microtubules in two ways. First, I am
interested in understanding how microtubules are regulated on a
molecular level, and how microtubule regulatory proteins are
controlled in different cell types. A second goal is to
understand how abnormalities in microtubule regulation lead to
errors in cell division, including cancer and aneuploidy.
Specifically, I would like to know when microtubule defects
occur during cancer progression and whether particular
microtubule defects correlate with cancer development,
aggressiveness, and response to treatment. I emphasize live cell
imaging as a means to better understand what is happening in
real time. I focus on proteins that bind to the plus ends of
microtubules, both for their potential role as regulators of
microtubule behavior, and as tools to highlight the dynamic
microtubule end. EB1 is an especially interesting protein of
this class, because it is highly conserved, it interacts with
the colon cancer tumor suppressor adenomatous polyposis coli (APC),
and it targets to kinetochores, where the microtubules attach to
the chromosomes, in a unique pattern. I am studying how EB1
interacts with microtubules and using EB1 as a tool to monitor
microtubule polymerization and organization in different cell
types.
Lab Rotation Projects
Microtubule Regulation in Normal and Cancer Cells
This is a new laboratory studying two related areas - the
basic regulation of microtubules during cell division, and how
microtubule defects contribute to epithelial cancers such as
colon cancer. We welcome students interested in all aspects of
cell division and cancer biology. Specific projects include but
are not limited to:
1) We want to understand how microtubules are
regulated in epithelial cells. Using a microtubule binding
assay, purify novel proteins bound to microtubules in polarized
epithelial cells. Use high resolution imaging to localize these
proteins during cell polarization and in cancer vs. normal
cells.
2) We have developed an assay for mitotic spindle
orientation in intact tumors and tissues. Compare tumors with
normal tissues to determine the role of tumor suppressors in
spindle orientation
3) We have shown a role for the colon cancer tumor
suppressor APC in spindle orientation. Dissect its mechanism in
a polarized tissue culture system using RNAi
4) Develop a project to help understand a basic
question in microtubule regulation. These include mechanisms of
dynamic instability, microtubule dynamics regulation during the
cell cycle, inter-relationships among microtubule plus end
binding proteins, and mechanisms of plus end binding.
Selected Publications
Fleming ES, Zajac M, Moschenross DM, Montrose DC, Rosenberg DW,
Cowan AE, and Tirnauer JS. . Planar Spindle Orientation and
Asymmetric Cytokinesis in the Mouse Small Intestine. Journal of
Histochemistry and Cytochemistry, 2007, 55 (11) 1173-80.
Canman, JC, Cameron, LA, Maddox, PS, Straight, A, Tirnauer,
JS, Mitchison, TJ, Fang, G, Kapoor, TM, Salmon, ED. Determining
the position of the cell division plane. Nature, 2003, 424:
1074-1078.
Carvalho P, Tirnauer JS, Pellman D. Surfing on Microtubule
Ends. Trends in Cell Biology, 2003, 13(5): 229-237.
Tirnauer JS, Canman JC, Salmon ED, Mitchison, TJ. EB1 Targets
to Kinetochores with Attached, Polymerizing Microtubules.
Molecular Biology of the Cell, 2002, 13 (12) 4308-4316.
Tirnauer JS, Grego S, Salmon ED, Mitchison TJ.
EB1-microtubule interactions in Xenopus egg extracts: role of
EB1 in microtubule stabilization and mechanisms of targeting to
microtubules. Molecular Biology of the Cell, 2002, 13 (10)
3614-3626.
Tirnauer JS, Bierer BE. EB1 Proteins Regulate Microtubule
Dynamics, Cell Polarity, and Chromosome Stability. The Journal
of Cell Biology, 2000; 149(4):761-6.
Lee L, Tirnauer JS, Li J, Schuyler SC, Liu J, Pellman D.
Positioning of the Mitotic Spindle by a Cortical-Microtubule
Capture Mechanism. Science, 2000, 287: 2260-2262.
Revised April, 2008. |
