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EWSR1 and FUS fusion genes in tumorigenesis

Möller, Emely LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:62.
Abstract
The present thesis concerns the involvement of EWSR1 and FUS fusion genes, and the chimeric proteins they encode, in tumorigenesis. In Article I, the EWSR1 promoter, which regulates the expression of EWSR1 fusion genes, was characterized and regions that were crucial for promoter activity could be identified. The sequence was found to have bidirectional activity and is likely to regulate also RHBDD3, another cancer-associated gene. In Article II, the EWSR1-POU5F1 fusion was found in hidradenoma and mucoepidermoid carcinoma, the first report of EWSR1 fusion genes in epithelial tumor types. The EWSR1-POU5F1 chimera was a stronger transcriptional activator than wild-type (wt) POU5F1, analogous to other EWSR1 chimeras, and was able to activate... (More)
The present thesis concerns the involvement of EWSR1 and FUS fusion genes, and the chimeric proteins they encode, in tumorigenesis. In Article I, the EWSR1 promoter, which regulates the expression of EWSR1 fusion genes, was characterized and regions that were crucial for promoter activity could be identified. The sequence was found to have bidirectional activity and is likely to regulate also RHBDD3, another cancer-associated gene. In Article II, the EWSR1-POU5F1 fusion was found in hidradenoma and mucoepidermoid carcinoma, the first report of EWSR1 fusion genes in epithelial tumor types. The EWSR1-POU5F1 chimera was a stronger transcriptional activator than wild-type (wt) POU5F1, analogous to other EWSR1 chimeras, and was able to activate transcription through a binding site which is normally recognized by POU5F1. In Article III, FUS-CREB3L2 was found to be a stronger transcriptional activator than wt CREB3L2 and to activate transcription through binding sites normally recognized by CREB3L2. Also, the results suggest that the chimera is regulated by intramembrane proteolysis like wt CREB3L2. In Article IV, low-grade fibromyxoid sarcoma (LGFMS), which is characterized by the FUS-CREB3L2 fusion, was found to have a specific gene expression profile, compared to histologically similar tumors types. Binding sites for FOXL1, the top upregulated gene in LGFMS, and other FOX factors were overrepresented in the promoters of LGFMS-upregulated genes, suggesting an important function of FOX factors in LGFMS.CD24 was upregulated in the tumors and FUS-CREB3L2 expressing cells, and FUS-CREB3L2 was able to activate transcription through a CD24 regulatory sequence. (Less)
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author
supervisor
opponent
  • Professor de Álava, Enrique, Laboratory of Molecular Pathology, Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Spain
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:62
pages
132 pages
publisher
Department of Clinical Genetics, Lund University
defense location
F1, Centralblocket
defense date
2010-05-27 09:30
ISSN
1652-8220
ISBN
978-91-86443-77-1
language
English
LU publication?
yes
id
63ea3610-8025-4907-b80c-3125e89dcd2a (old id 1599164)
date added to LUP
2010-05-05 08:37:16
date last changed
2018-05-29 12:28:45
@phdthesis{63ea3610-8025-4907-b80c-3125e89dcd2a,
  abstract     = {The present thesis concerns the involvement of EWSR1 and FUS fusion genes, and the chimeric proteins they encode, in tumorigenesis. In Article I, the EWSR1 promoter, which regulates the expression of EWSR1 fusion genes, was characterized and regions that were crucial for promoter activity could be identified. The sequence was found to have bidirectional activity and is likely to regulate also RHBDD3, another cancer-associated gene. In Article II, the EWSR1-POU5F1 fusion was found in hidradenoma and mucoepidermoid carcinoma, the first report of EWSR1 fusion genes in epithelial tumor types. The EWSR1-POU5F1 chimera was a stronger transcriptional activator than wild-type (wt) POU5F1, analogous to other EWSR1 chimeras, and was able to activate transcription through a binding site which is normally recognized by POU5F1. In Article III, FUS-CREB3L2 was found to be a stronger transcriptional activator than wt CREB3L2 and to activate transcription through binding sites normally recognized by CREB3L2. Also, the results suggest that the chimera is regulated by intramembrane proteolysis like wt CREB3L2. In Article IV, low-grade fibromyxoid sarcoma (LGFMS), which is characterized by the FUS-CREB3L2 fusion, was found to have a specific gene expression profile, compared to histologically similar tumors types. Binding sites for FOXL1, the top upregulated gene in LGFMS, and other FOX factors were overrepresented in the promoters of LGFMS-upregulated genes, suggesting an important function of FOX factors in LGFMS.CD24 was upregulated in the tumors and FUS-CREB3L2 expressing cells, and FUS-CREB3L2 was able to activate transcription through a CD24 regulatory sequence.},
  author       = {Möller, Emely},
  isbn         = {978-91-86443-77-1},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {132},
  publisher    = {Department of Clinical Genetics, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {EWSR1 and FUS fusion genes in tumorigenesis},
  volume       = {2010:62},
  year         = {2010},
}