Shwachman-Bodian-Diamond syndrome (SBDS) protein deficiency impairs translation re-initiation from C/EBPα and C/EBPß mRNAs.

Mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene cause Shwachman-Diamond Syndrome (SDS), a rare congenital disease characterized by bone marrow failure with neutropenia, exocrine pancreatic dysfunction and skeletal abnormalities. The SBDS protein is important for ribosome maturation and therefore SDS belongs to the ribosomopathies. It is unknown, however, if loss of SBDS functionality affects the translation of specific mRNAs and whether this could play a role in the development of the clinical features of SDS. Here, we report that translation of the C/EBPα and -ß mRNAs, that are indispensible regulators of granulocytic differentiation, is altered by SBDS mutations or knockdown. We show that SBDS function is specifically required for efficient translation re-initiation into the protein isoforms C/EBPα-p30 and C/EBPß-LIP, which is controlled by a single cis-regulatory upstream open reading frame (uORF) in the 5' untranslated regions (5' UTRs) of both mRNAs. Furthermore, we show that as a consequence of the C/EBPα and -ß deregulation the expression of MYC is decreased with associated reduction in proliferation, suggesting that failure of progenitor proliferation contributes to the haematological phenotype of SDS. Therefore, our study provides the first indication that disturbance of specific translation by loss of SBDS function may contribute to the development of the SDS phenotype.

Resveratrol at high doses acts as an apoptotic inducer in endothelial cells.

PURPOSES: Resveratrol is a phenolic compound found in grapes and other food products. In order to assess the availability of resveratrol as an angio-inhibiting drug, we examined whether resveratrol plays an important role in bovine aortic endothelial cells (BAECs) for cell apoptosis and cell migration. METHODS AND MATERIALS: Endothelial cell apoptosis was observed as detected by the Hoechst staining and the caspase-3 activity. Additionally, Western blotting was performed for monitoring the activities of various cell signaling molecules. RESULTS: Resveratrol was shown to act as a pro-apoptotic agent. The pro-apoptotic effect of resveratrol was as great as that of etoposide, a well-known anti-cancer drug. In addition, resveratrol had an inhibitory effect on endothelial cell migration. The demonstrated efficacy of resveratrol suggests that resveratrol may be utilized as an anti-angiogenic drug. To determine the underlying mechanisms, we further investigated which signaling molecules are activated by resveratrol. Extracellular signal-regulated kinase (ERK) was activated by the treatment with resveratrol in BAECs, whereas endothelial nitric oxide synthetase (eNOS), Akt, and Jun N-terminal kinase (JNK) were inhibited. The pretreatment with PD compound, an ERK inhibitor, had no effect on the pro-apoptosis induced by resveratrol. CONCLUSION: Resveratrol plays an important role in endothelial cell apoptosis, indicating that resveratrol can be utilized as a potent anti-angiogenic drug.