1999 Fiscal Year Final Research Report Summary
Isolation and characterization of Peutz-Jeghers Syndrome Gene
| Project/Area Number |
10671180
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Japanese Foundation for Cancer Research (1999)
Osaka University (1998) |
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Principal Investigator |
KOYAMA Kumiko Department of Human Genome Analysis, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Research Associate, 癌化学療法センター・ゲノム解析研究部, 研究員 (90294066)
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| Co-Investigator(Kenkyū-buntansha) |
KURAHASHI Hiroki Osaka University Medical Schoo., Research Associate, 医学部, 助手 (30243215)
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| Project Period (FY) |
1998 – 1999
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| Keywords | PJS / STK11 / LKB1 / Mutation search / APCL / 53BP2 / EB1 / EB3 |
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| Research Abstract |
1. We isolated a novel gene, APCL that showed significant homology to the adenomatous polyposis coli (APC) tumor suppressor gene. This novel gene located on chromosome 19p13.3, which region is STK11/LKB1 gene that cause of Peutz-Jeghers Syndrome (PJS). APCL encodes a protein of 2303 amino acids that is expressed specifically in the brain. The heptad-repeat domain found in the APC protein is well conserved in APCL (45% of the amino acids are identical) ; therefore APCL is likely also to form homo- or hetero- dimers Moreover, since the Armadillo domain is also well conserved (76% identical), both proteins may interact with the same or similar molecular entities. The central portion of APCL consists of five copies of a 20-amino-acid motif and we showed earlier that through this domain APCL could interact with beta-catenin and deplete its intracellular concentration. However, as the C-terminus of APCL protein bears little similarity to that of APC (only 13% identical amino acids), that par
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t of the molecule can be presumed to interact with different proteins ; if so, APCL would possess at least some functions distinct from those of APC. Using a yast two-hybrid system, we attempted to isolate proteins that might associate with the unique COOH-terminus of APCL. Among 166 cDNA clones isolated from a human fetal-brain cDNA library as candidates for interaction with APCL, 32 encoded parts of p53-binding protein 2 (53BP2), a molecule that interacts with p53 and Bcl2, six included an identical sequence with significant homology to EB1, a protein known to bind to APC.
2. We investigated the entrie cording of STK11 in 68 patients of 20 unrelated PJS families by the PCR-SSCP method and PCR-direct sequence analysis, and found 15 different, mutations among 14 of those families. One nonsense mutation and eight different frameshift mutations, all of which would cause truncation of the gene product. Moreover three carried intronic mutations at or adjacent to the consensus dinucleotide sequence of splice-acceptor or-donor sites, which were likely to lead to aberrantsplicing. Less
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Research Products
(12 results)
