Mouse modifiers of intestinal tumorigenesis
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 2001.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2005
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| Online Access: | http://hdl.handle.net/1721.1/8585 |
| _version_ | 1811077254642401280 |
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| author | Hong, Karen H. (Karen Hsiao-Ying), 1971- |
| author2 | Eric S. Lander. |
| author_facet | Eric S. Lander. Hong, Karen H. (Karen Hsiao-Ying), 1971- |
| author_sort | Hong, Karen H. (Karen Hsiao-Ying), 1971- |
| collection | MIT |
| description | Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 2001. |
| first_indexed | 2024-09-23T10:40:07Z |
| format | Thesis |
| id | mit-1721.1/8585 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T10:40:07Z |
| publishDate | 2005 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/85852019-04-10T09:18:16Z Mouse modifiers of intestinal tumorigenesis Hong, Karen H. (Karen Hsiao-Ying), 1971- Eric S. Lander. Massachusetts Institute of Technology. Dept. of Biology. Massachusetts Institute of Technology. Dept. of Biology. Biology. Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 2001. Includes bibliographical references. Colorectal cancer involves a series of molecular alterations as a normal cell progresses to malignancy. A large body of evidence points to the mutation of the APC gene as the pivotal event initiating intestinal tumorigenesis. Apdmin, an induced mutation in mouse homologue of APC, was identified several years ago by Moser et al., providing a genetic model system to study this process. We used the Apdmin system to identify additional genes influencing tumorigenesis. One of these genes,. Mom1 (Modifier of Min-1), involves the effect of genetic background on the Apdmin phenotype. On C57BL/6 (B6), the strain on which Apdmin arose, mice develop approximately 100 tumors. However, B6 X AKR Fl hybrids develop five-fold fewer tumors. Mom1 was identified as the major locus controlling this variation and localized to a 15 cM region on distal mouse chromosome 4 by Dietrich et al. To positionally clone Mom1, Gould et al created a B6.Mom1 AKR congenic strain isolating Mom1 from other AKR resistance factors. Separated from other loci, a single copy of Mom1 AKR reduced tumor number by 50% and two copies produced a 70% reduction. We have used recombinant lines derived from B6.Mom1 AKR to mapMom1 to a 4-cM interval containing one candidate gene, the group IIA secretory phospholipase a2 (sPLA2-IIA). Only tumor prone Mom1 strains, such as B6, contain a mutation in sPLA2-IIA abolishing expression. In order to rigorously measure the effect of sPLA2-IIA on the Apdmin tumor phenotype, we have created and analyzed transgenic lines that restore sPLA2-IIA expression. While we conclude that sPLA2-IIA is indeed protective, tumor number is only reduced by approximately 30%, suggesting that sPLA2-IIA is only part of Mom1. Analysis of additional Moml AKR recombinant strains containing and lacking sPLA2-IIA also implicates a separate distal modifier that accounts for the remaining resistance. To further probe how phospholipases impinge on intestinal cancers, we have studied tumorigen-sis in mice lacking group IV cytosolic phospholipase a2 (cPLA2). Crossing ApcMin into this background produces an 83% reduction in tumor number in ApcMin, cPLA2 -/- homozygotes, suggesting that cPLA2 expression promotes tumorigenesis, most likely via the production of arachidonic acid for downstream eicosanoid synthesis. by Karen H. Hong. Ph.D. 2005-08-23T21:29:25Z 2005-08-23T21:29:25Z 2001 2001 Thesis http://hdl.handle.net/1721.1/8585 49265119 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 89, [6] leaves 11531312 bytes 11531072 bytes application/pdf application/pdf application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Hong, Karen H. (Karen Hsiao-Ying), 1971- Mouse modifiers of intestinal tumorigenesis |
| title | Mouse modifiers of intestinal tumorigenesis |
| title_full | Mouse modifiers of intestinal tumorigenesis |
| title_fullStr | Mouse modifiers of intestinal tumorigenesis |
| title_full_unstemmed | Mouse modifiers of intestinal tumorigenesis |
| title_short | Mouse modifiers of intestinal tumorigenesis |
| title_sort | mouse modifiers of intestinal tumorigenesis |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/8585 |
| work_keys_str_mv | AT hongkarenhkarenhsiaoying1971 mousemodifiersofintestinaltumorigenesis |