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Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond–Blackfan anemia
- Source :
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1792:1036-1042
- Publication Year :
- 2009
- Publisher :
- Elsevier BV, 2009.
-
Abstract
- Diamond–Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblasts from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.
- Subjects :
- Diamond–Blackfan anemia
Ribosomal Proteins
Congenital Anemia
Cell cycle checkpoint
RPS19
Proliferation
Blotting, Western
Mutant
Down-Regulation
Cell Cycle Proteins
Article
03 medical and health sciences
0302 clinical medicine
Ribosomal protein S19
medicine
Humans
Molecular Biology
Cells, Cultured
Anemia, Diamond-Blackfan
Cell Proliferation
030304 developmental biology
0303 health sciences
biology
Cell Cycle
Cyclin-dependent kinase 2
Fibroblasts
Cell cycle
medicine.disease
Molecular biology
RNA, Ribosomal
030220 oncology & carcinogenesis
Mutation
Cancer research
biology.protein
Molecular Medicine
RPS24
Cyclin-dependent kinase 6
Cell cycle regulation
Subjects
Details
- ISSN :
- 09254439
- Volume :
- 1792
- Database :
- OpenAIRE
- Journal :
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Accession number :
- edsair.doi.dedup.....96c8114fb220204775d14970f1635e39