EWSR1 and FUS fusion genes in tumorigenesis
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1599164
- author
- Möller, Emely LU
- supervisor
-
- Fredrik Mertens LU
- Nils Mandahl LU
- Thoas Fioretos LU
- opponent
-
- Professor de Álava, Enrique, Laboratory of Molecular Pathology, Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Spain
- organization
- publishing date
- 2010
- 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 09:30:00
- 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
- 2016-04-01 14:32:47
- date last changed
- 2023-04-18 20:12:36
@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}}, 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}}, url = {{https://lup.lub.lu.se/search/files/4032128/1599189.pdf}}, volume = {{2010:62}}, year = {{2010}}, }