Down-Regulation of Ubiquitin Ligase Cbl Induced by Twist Haploinsufficiency in Saethre-Chotzen Syndrome Results in Increased PI3K/Akt Signaling and Osteoblast Proliferation
| Autor: | Hichem Miraoui, Pierre J. Marie, Hind Guenou, Karim Kaabeche, Cécilie Dufour |
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| Rok vydání: | 2006 |
| Předmět: |
Down-Regulation
Transfection Pathology and Forensic Medicine Phosphatidylinositol 3-Kinases Twist transcription factor medicine Humans Proto-Oncogene Proteins c-cbl Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Osteoblasts biology Ubiquitin Twist-Related Protein 1 Nuclear Proteins Osteoblast Cranial Sutures Acrocephalosyndactylia medicine.disease Ubiquitin ligase medicine.anatomical_structure biology.protein Cancer research Saethre–Chotzen syndrome Signal transduction Haploinsufficiency Proto-Oncogene Proteins c-akt Signal Transduction Regular Articles |
| Zdroj: | The American Journal of Pathology. 169:1303-1311 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2006.060102 |
| Popis: | Genetic mutations of Twist, a basic helix-loop-helix transcription factor, induce premature fusion of cranial sutures in Saethre-Chotzen syndrome (SCS). We report here a previously undescribed mechanism involved in the altered osteoblastogenesis in SCS. Cranial osteoblasts from an SCS patient with a Twist mutation causing basic helix-loop-helix deletion exhibited decreased expression of E3 ubiquitin ligase Cbl compared with wild-type osteoblasts. This was associated with decreased ubiquitin-mediated degradation of phosphatidyl inositol 3 kinase (PI3K) and increased PI3K expression and PI3K/Akt signaling. Increased PI3K immunoreactivity was also found in osteoblasts in histological sections of affected cranial sutures from SCS patients. Transfection with Twist or Cbl abolished the increased PI3K/Akt signaling in Twist mutant osteoblasts. Forced overexpression of Cbl did not correct the altered expression of osteoblast differentiation markers in Twist mutant cells. In contrast, pharmacological inhibition of PI3K/Akt, but not ERK signaling, corrected the increased cell growth in Twist mutant osteoblasts. The results show that Twist haploinsufficiency results in decreased Cbl-mediated PI3K degradation in osteoblasts, causing PI3K accumulation and activation of PI3K/Akt-dependent osteoblast growth. This provides genetic and biochemical evidence for a role for Cbl-mediated PI3K signaling in the altered osteoblast phenotype induced by Twist haploinsufficiency in SCS. |
| Databáze: | OpenAIRE |
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