| Autor: |
Aziz K; Department of Biochemistry and Molecular Biology and., Sieben CJ; Department of Biochemistry and Molecular Biology and., Jeganathan KB; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA., Hamada M; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA., Davies BA; Department of Biochemistry and Molecular Biology and., Velasco ROF; Department of Biochemistry and Molecular Biology and., Rahman N; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom., Katzmann DJ; Department of Biochemistry and Molecular Biology and., van Deursen JM; Department of Biochemistry and Molecular Biology and.; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA. |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of clinical investigation [J Clin Invest] 2018 Aug 01; Vol. 128 (8), pp. 3517-3534. Date of Electronic Publication: 2018 Jul 23. |
| DOI: |
10.1172/JCI120316 |
| Abstrakt: |
A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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