2016
DOI: 10.1038/srep33165
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New insights into the Shwachman-Diamond Syndrome-related haematological disorder: hyper-activation of mTOR and STAT3 in leukocytes

Abstract: Shwachman-Diamond syndrome (SDS) is an inherited disease caused by mutations of a gene encoding for SBDS protein. So far little is known about SBDS exact function. SDS patients present several hematological disorders, including neutropenia and myelodysplastic syndrome (MDS), with increased risk of leukemic evolution. So far, the molecular mechanisms that underlie neutropenia, MDS and AML in SDS patients have been poorly investigated. STAT3 is a key regulator of several cellular processes including survival, di… Show more

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Cited by 26 publications
(45 citation statements)
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References 52 publications
(69 reference statements)
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“…Rare mutations implicated in stomach cancer affect residues that might be essential for this RPSA function (12). Additionally, the recent observation of elevated STAT3 and mTOR phosphorylation levels in leukocytes from SDS patients reflects a potential novel extra-ribosomal link between SBDS and mTOR/STAT3 (159). The increased ROS levels and autophagy phenotypes observed in zebrafish models of several DBA RPs including RPS19 may also reflect novel extra-ribosomal functions (160).…”
Section: Defects In Ribosome Biogenesis Ribosomal Proteins and Ribosmentioning
confidence: 99%
“…Rare mutations implicated in stomach cancer affect residues that might be essential for this RPSA function (12). Additionally, the recent observation of elevated STAT3 and mTOR phosphorylation levels in leukocytes from SDS patients reflects a potential novel extra-ribosomal link between SBDS and mTOR/STAT3 (159). The increased ROS levels and autophagy phenotypes observed in zebrafish models of several DBA RPs including RPS19 may also reflect novel extra-ribosomal functions (160).…”
Section: Defects In Ribosome Biogenesis Ribosomal Proteins and Ribosmentioning
confidence: 99%
“…The deletion of T117 may affect GTP binding through rearrangements of residues 113-116, but this is difficult to predict. 4 0 9 5 jci.org Volume 127 Number 11 November 2017 in 2 cell lines (HeLa and HL60), it had no impact on the expression of 2 other proteins known to be mutated in SDS (i.e., SBDS and DNAJC21) (Supplemental Figure 6) or on the mTOR pathway, which was previously linked to SDS pathophysiology (23,24). Zebrafish model.…”
mentioning
confidence: 95%
“…LCLs were obtained from patients carrying the c.[183–184TA > CT] nonsense mutation as previously described . 2 × 10 6 LCLs were incubated in RPMI‐1640 medium containing 0.5% fetal bovine serum (FBS) (Biosera, Ringmer, UK) for 24 hours, to synchronize cell growth.…”
Section: Methodsmentioning
confidence: 99%
“…LCLs were seeded at 2.5 × 10 5 cells in 4 aliquots and incubated at 37°C in the presence or absence of increasing concentrations of ataluren, as indicated, for 24–72 hours. LCLs were fixed in 2% paraformaldehyde and permeabilized in 100% ice‐cold methanol, washed twice in flow buffer (PBS, pH 7.2, with 0.2% BSA and 0.09% sodium azide) as previously described and then stained with anti‐p‐S2448‐mTOR‐PE or isotype control‐PE (Becton‐Dickinson Biosciences, Franklin Lakes, New Jersey) for 30 minutes. Cells were washed and acquired on a 10 color, 3 laser (Blue Solid State Diode: 488 nm, 22 mW, Red Solid State Diode: 638 nm, 25 mW, Violet Solid State Diode: 405 nm, 40 mW), Navios flow cytometer (Beckman Coulter, Indianapolis, Indiana).…”
Section: Methodsmentioning
confidence: 99%
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