Studies on signals mediating or preventing the intracrine induction of chromatin compaction and cell death by high molecular weight fibroblast growth factor 2
| dc.contributor.author | Ma, Xin | |
| dc.contributor.examiningcommittee | Davie, James(Biochemistry and Medical Genetics) Anderson, Judith(Biological Sciences) Kong, Jiming(Human Anatomy & Cell Sciences) | en |
| dc.contributor.supervisor | Kardami, Elissavet (Human Anatomy & Cell Sciences) | en |
| dc.date.accessioned | 2011-04-05T20:03:50Z | |
| dc.date.available | 2011-04-05T20:03:50Z | |
| dc.date.issued | 2011-04-05T20:03:50Z | |
| dc.degree.discipline | Human Anatomy and Cell Science | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Fibroblast growth factor 2 (FGF2) is a multifunctional protein translated as CUG-initiated, high molecular weight (hi FGF2) or AUG-initiated, low molecular weight (lo FGF2) isoforms with potentially distinct functions. Previous work showed that overexpression of hi- but not lo FGF2 elicited chromatin compaction resulting in cell death, by an intracrine route. A series of studies were undertaken aimed at extending our understanding of the intracrine action of Hi FGF2. Major findings are as follows: a. Hi FGF2 overexpression induces apoptotic cell death, as indicated by increased TUNEL staining, and mitochondrial participation (cytochrome c release to cytosol, rescue of the hi FGF2 phenotype by the anti-apoptotic protein Bcl-2. b. Increased expression of pro-survival signals/proteins that are known to upregulate Bcl-2, such as nuclear Akt; the PIM-1 kinase; and the heat shock protein hsp70, also rescued the hi FGF2-induced phenotype. c. The hi-FGF2 effect was associated with sustained, intracrine, activation of ERK, and was blocked by ERK inhibitors. d. FGF2 isoform specific affinity chromatography followed by mass spectroscopy identified several proteins as potentially interacting with hi FGF2; of these, the p68 RNA helicase and the hsp70 were further confirmed as interacting partners, by co-immunoprecipitation. e. Increased nuclear co-localization, and possibly interaction, between hi FGF2 and overexpressed hsp70 correlated with rescue from hi FGF2 induced cell death. f. Factors associated with cardiac pathology (isoproterenol, angiotensin II, endothelin I) also upregulated endogenous hi FGF2 in cardiac cells in culture. Adriamycin-induced cardiotoxicity in the rat, known to be linked to increased incidence of apoptosis, was also associated with increased endogenous hi FGF2. g. Hi FGF2 is expressed in the human heart (atria) and localizes in both cytosol and nuclei, suggesting a participation in human heart physiology and pathophysiology. Work presented here is consistent with the notion that endogenous hi FGF2 up-regulation may play a role in promoting cell death during prolonged tissue stress and dysfunction. It follows that processes related to hi FGF2 upregulation, hi FGF2-nuclear protein interactions and mechanisms of hi FGF2 induced cell death, represent potential therapeutic targets for modulating cell death. | en |
| dc.description.note | May 2011 | en |
| dc.format.extent | 4887310 bytes | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.citation | Kardami E, Detillieux K, Ma X, Jiang Z, Santiago JJ, Jimenez SK, Cattini PA. (2007). Heart Fail Review 12(3-4):267-77. | en |
| dc.identifier.citation | Ma X, Dang X, Claus P, Hirst C, Fandrich RR, Jin Y, Grothe C, Kirshenbaum LA, Cattini PA, Kardami E. (2007). Journal of Cellular Physiology 213(3):690-8. | en |
| dc.identifier.citation | Santiago JJ, Ma X, McNaughton LJ, Nickel BE, Bestvater BP, Yu L, Fandrich RR, Netticadan T, Kardami E. (2010). Cardiovascular Research 89(1):139-47. | en |
| dc.identifier.uri | http://hdl.handle.net/1993/4439 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | high molecular weight fibroblast growth factor 2 | en |
| dc.subject | chromatin compaction | en |
| dc.subject | apoptotic cell death | en |
| dc.subject | intracrine | en |
| dc.title | Studies on signals mediating or preventing the intracrine induction of chromatin compaction and cell death by high molecular weight fibroblast growth factor 2 | en |
| dc.type | doctoral thesis | en_US |