Down-regulation of ubiquitin ligase Cbl induced by twist haploinsufficiency in Saethre-Chotzen syndrome results in increased PI3K/Akt signaling and osteoblast proliferation.

Abstract

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.

• Authors: Hind Guenou, Karim Kaabeche, Cécilie Dufour, Hichem Miraoui, Pierre J Marie
• Journal: The American journal of pathology (Am J Pathol) Vol. 169 Issue 4 Pg. 1303-11 (Oct 2006) ISSN: 0002-9440 [Print] United States
• PMID: 17003487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• TWIST1 protein, human
• Twist-Related Protein 1
• Ubiquitin
• Proto-Oncogene Proteins c-cbl
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Acrocephalosyndactylia (enzymology, genetics)
• Cell Proliferation
• Cranial Sutures (enzymology)
• Down-Regulation
• Humans
• Nuclear Proteins (deficiency, genetics)
• Osteoblasts (cytology, enzymology)
• Phosphatidylinositol 3-Kinases (analysis, metabolism)
• Proto-Oncogene Proteins c-akt (analysis, metabolism)
• Proto-Oncogene Proteins c-cbl (genetics, metabolism)
• Signal Transduction
• Transfection
• Twist-Related Protein 1 (deficiency, genetics)
• Ubiquitin (metabolism)