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The Single Minded 2 Gene (SIM2) and Cancer: Harnessing Micro-Array Data to Facilitate Pathway Discovery and Validation
| Title: | The Single Minded 2 Gene (SIM2) and Cancer: Harnessing Micro-Array Data to Facilitate Pathway Discovery and Validation. |
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| Name(s): |
Aleman, Mireille J., author Narayanan, Ramaswamy, Thesis advisor Florida Atlantic University, Degree grantor |
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| Type of Resource: | text | |
| Genre: | Electronic Thesis Or Dissertation | |
| Date Created: | 2007 | |
| Date Issued: | 2007 | |
| Publisher: | Florida Atlantic University | |
| Place of Publication: | Boca Raton, Fla. | |
| Physical Form: | application/pdf | |
| Extent: | 166 p. | |
| Language(s): | English | |
| Summary: | A Down's Syndrome related Single Minded 2 gene (SIM2), previously known to be associated with Trisomy 21 was predicted by bioinformatics to be colon cancer specific. In previous work from the laboratory using a patient tissue repository, an isoform of this gene, short form (SIM2-s) was shown to be colon cancer specific. Inhibition of SIM2-s expression by antisense technology resulted in cancer-cell specific apoptosis within 24 hours. Microarray-based gene expression profiling of the antisense-treated colon cancer cells provided a fingerprint of genes involving key cell cycle, apoptosis, DNA damage and differentiation genes. Taking hints from the microarray database, experiments were initiated to decipher the molecular mechanism underlying the cancer specific function of the SIM2-s gene. Using an isogenic cell system, apoptosis was found to be dependent on DNA damage and repair gene, GADD45-a. Further, key pathways including p38 MAP kinase (MAPK) and specific caspases were essential for apoptosis. Programmed cell death was not dependant on cell cycle and was preceded by the induction of terminal differentiation. To clarify whether SIM2-s function is a critical determinant of differentiation, stable transfectants of SIM2-s were established in a murine adipocytic cell line (3T3-L 1 ). SIM2-s overexpression caused a pronounced block of differentiation of the pre-adipocytes into mature adipocytes. A study of the differentiation pathway in 3T3-L 1 cells suggested that this block occurs early on in the cascade. These results supported the starting premise that SIM2-s is a critical mediator of cell differentiation. To clarify whether the SIM2-s gene has transforming potential, the SIM2-s gene was overexpressed in the NIH3T3 murine fibroblast cell line. The cells expressing the human SIM2-s gene exhibited shorter doubling time, abrogation of growth serum requirement, greater cell number at saturation density and focus formation. In vivo tumorigenicity assays showed tumor formation with long latency. These results provide strong evidence for the role of SIM2-s gene in tumor cell growth and differentiation, and validate drug therapy use for the gene. | |
| Identifier: | FA00000845 (IID) | |
| Degree granted: | Dissertation (Ph.D.)--Florida Atlantic University, 2007. | |
| Subject(s): |
Cancer--Genetic aspects DNA microarrays--Diagnostic use Apoptosis--Molecular aspects Medical informatics Gene expression--Research--Methodology |
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| Held by: | Florida Atlantic University Libraries | |
| Sublocation: | Digital Library | |
| Persistent Link to This Record: | http://purl.flvc.org/fau/fd/FA00000845 | |
| Use and Reproduction: | Copyright © is held by the author with permission granted to Florida Atlantic University to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder. | |
| Use and Reproduction: | http://rightsstatements.org/vocab/InC/1.0/ | |
| Host Institution: | FAU | |
| Is Part of Series: | Florida Atlantic University Digital Library Collections. |
