H255Y and K508R missense mutations in tumour suppressorfolliculin (FLCN)promote kidney cell proliferation
| العنوان: | H255Y and K508R missense mutations in tumour suppressorfolliculin (FLCN)promote kidney cell proliferation |
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| المؤلفون: | Yukiko Hasumi, W. Marston Linehan, Laura S. Schmidt, Ming Hui Wei, Masaya Baba, Maria J. Merino, Martin Lang, Lionel Feigenbaum, Kazuhide Makiyama, Yasuhiro Isono, Adam R. Metwalli, Hafumi Nishi, Hisashi Hasumi, Andrew C. Warner, Berton Zbar, Cathy D. Vocke, Keiichi Kondo, Takashi Kawahara, Noboru Nakaigawa, Mitsuko Furuya, Diana C. Haines, Nobuko Irie, Masahiro Yao, Herbert Hagenau, Chiharu Esumi |
| المصدر: | Human Molecular Genetics. :ddw392 |
| بيانات النشر: | Oxford University Press (OUP), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Transgene, Mutation, Missense, Cardiomegaly, Biology, Kidney, medicine.disease_cause, Birt–Hogg–Dubé syndrome, Birt-Hogg-Dube Syndrome, Mice, 03 medical and health sciences, Germline mutation, Proto-Oncogene Proteins, Genetics, medicine, Animals, Humans, Missense mutation, Folliculin, Molecular Biology, Germ-Line Mutation, Genetics (clinical), Cell Proliferation, Mice, Knockout, Mutation, Tumor Suppressor Proteins, Articles, General Medicine, Kidney Diseases, Cystic, medicine.disease, Phenotype, Kidney Neoplasms, Gene Expression Regulation, Neoplastic, Disease Models, Animal, 030104 developmental biology, Knockout mouse, Cancer research |
| الوصف: | Germline H255Y and K508R missense mutations in the folliculin (FLCN) gene have been identified in patients with bilateral multifocal (BMF) kidney tumours and clinical manifestations of Birt-Hogg-Dubé (BHD) syndrome, or with BMF kidney tumours as the only manifestation; however, their impact on FLCN function remains to be determined. In order to determine if FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation leading to pathogenicity, we generated mouse models expressing these mutants using BAC recombineering technology and investigated their ability to rescue the multi-cystic phenotype of Flcn-deficient mouse kidneys. Flcn H255Y mutant transgene expression in kidney-targeted Flcn knockout mice did not rescue the multi-cystic kidney phenotype. However, expression of the Flcn K508R mutant transgene partially, but not completely, abrogated the phenotype. Notably, expression of the Flcn K508R mutant transgene in heterozygous Flcn knockout mice resulted in development of multi-cystic kidneys and cardiac hypertrophy in some mice. These results demonstrate that both FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation, but to different degrees. Based on the phenotypes of our preclinical models, the FLCN H255Y mutant protein has lost it tumour suppressive function leading to the clinical manifestations of BHD, whereas the FLCN K508R mutant protein may have a dominant negative effect on the function of wild-type FLCN in regulating kidney cell proliferation and, therefore, act as an oncoprotein. These findings may provide mechanistic insight into the role of FLCN in regulating kidney cell proliferation and facilitate the development of novel therapeutics for FLCN-deficient kidney cancer. |
| تدمد: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddw392 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fb8cfb90089a6e7c436be11ea19b004c https://doi.org/10.1093/hmg/ddw392 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fb8cfb90089a6e7c436be11ea19b004c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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| DOI: | 10.1093/hmg/ddw392 |