Centrosome protein fusions and leukemia
- Joanna Y. Lee.
- Aug. 2012.
- Physical description
- online resource (vi, 97 pages) : illustrations (some color)
- Lee, Joanna Yingtyan.
- Ferrell, James Ellsworth. thesis advisor.
- Kopito, Ron Rieger thesis advisor.
- Nelson, W. J. (W. James) thesis advisor.
- Stearns, Tim. thesis advisor (primary).
- Stanford University. Department of Biological Sciences.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references.
- Chromosomal translocations fusing genes that encode centrosome proteins and tyrosine kinases are frequently observed in myeloproliferative neoplasms (MPNs). Although the function of centrosome proteins in these fusions is not well understood, roles that may contribute to proliferative signaling including kinase centrosome localization and constitutive kinase dimerization have long been postulated. To test the relative contributions of localization and dimerization on kinase signaling efficiency, we targeted inducibly dimerizable FGFR1 to several subcellular locations and generated a centrosome localization mutant of the FOP-FGFR1 MPN fusion. Expression in mammalian tissue culture cells followed by substrate phosphorylation assays reveals a statistically significant decrease in kinase signaling effectiveness upon loss of FOP-FGFR1 centrosome localization. Interestingly, wild-type FOP-FGFR1 expression also caused a centrosome localization-dependent ciliogenesis defect. Further studies revealed that the fusion partner, FOP, localizes to centriolar satellites in addition to its previously described centrosomal localization. Centriolar satellites are granules clustered around the centrosome suspected to function in microtubule anchoring, protein trafficking, and ciliogenesis, though their precise function and composition remain unknown. Satellite localization is retained in the FOP-FGFR1 fusion and an increase in phosphotyrosine activity occurs at satellites in FOP-FGFR1 expressing cells. Given the importance of centriolar satellites in ciliogenesis, and the link between ciliogenesis and proliferative signaling, it is possible that increased phosphotyrosine activity at satellites is functionally significant in the progression of MPN. Finally, we assayed for ciliary signaling proteins in chronic myelogenous leukemia (CML) cells. Although FOP-FGFR1 causes a ciliogenesis defect, MPN affects blood cells, which have not been reported to contain cilia. We show here that, although CML cells do not appear to form a primary cilium, they contain masses of stabilized tubulin that co-localize with ciliary proteins. This may be evidence for a form of ciliary signaling in unciliated mammalian cells.
- Publication date
- Submitted to the Department of Biological Sciences and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2012.