Bartoli, Kristen Marie
(2010)
DISCOVERY AND CHARACTERIZATION OF THE INTERPHASE FUNCTION OF MITOTIC MOTORS IN PROTEIN SYNTHESIS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Mitotic motors have gained considerable interest as anticancer targets given their often essential functions during mitosis. Furthermore, mitotic motors are thought to represent ideal targets because their functions are believed to be confined to mitosis; thus, only rapidly dividing cells would be susceptible to inhibitors of mitotic motors. The work presented herein challenges the concept of mitotic motors as specific targets of dividing cells by exploring the interphase function of three mitotic motors Kid, Eg5, and MKLP1. Our results demonstrate that all three motors associate with the nucleolus and with the ribosomal subunits. Furthermore, it is demonstrated Eg5 functions to increase the processivity of the ribosome, the first cellular factor to be characterized with that property. Additionally, as loss of Kid results in an increase in focal adhesion proteins throughout the cell and increased protein synthesis in its absence, our data are consistent with a role for Kid in mRNA silencing and transport of mRNAs for site-specific translation. Also, evidence is presented that suggests a role for Kid in ribosome biogenesis and/or ribosomal function, similar to nucleophosmin. Finally, both Kid and Eg5 participate in stress granule dynamics, with Kid and Eg5 functioning in stress granule formation, and Eg5 participating in stress granule coalescence, transport and dissolution. Collectively these findings demonstrate diverse interphase functions for these mitotic motors in nearly all phases of the ribosome's life cycle. These studies not only call into question the potential safety of mitotic motor inhibitors for the treatment of cancer, but also open a new avenue of exploring polypeptide synthesis.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
9 December 2010 |
| Date Type: |
Completion |
| Defense Date: |
2 September 2010 |
| Approval Date: |
9 December 2010 |
| Submission Date: |
7 December 2010 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Biochemistry and Molecular Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
; Eg5; Kid; mitotic motors; monastrol; protein synthesis; ribosomes; stress granules |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-12072010-180919/, etd-12072010-180919 |
| Date Deposited: |
10 Nov 2011 20:09 |
| Last Modified: |
15 Nov 2016 13:53 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10169 |
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