PMID- 22090422
OWN - NLM
STAT- MEDLINE
DCOM- 20120705
LR  - 20211203
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 21
IP  - 5
DP  - 2012 Mar 1
TI  - Tuberin and PRAS40 are anti-apoptotic gatekeepers during early human amniotic 
      fluid stem-cell differentiation.
PG  - 1049-61
LID - 10.1093/hmg/ddr535 [doi]
AB  - Embryoid bodies (EBs) are three-dimensional multicellular aggregates allowing the 
      in vitro investigation of stem-cell differentiation processes mimicking early 
      embryogenesis. Human amniotic fluid stem (AFS) cells harbor high proliferation 
      potential, do not raise the ethical issues of embryonic stem cells, have a lower 
      risk for tumor development, do not need exogenic induction of pluripotency and 
      are chromosomal stable. Starting from a single human AFS cell, EBs can be formed 
      accompanied by the differentiation into cells of all three embryonic germ layers. 
      Here, we report that siRNA-mediated knockdown of the endogenous tuberous 
      sclerosis complex-2 (TSC2) gene product tuberin or of proline-rich Akt substrate 
      of 40 kDa (PRAS40), the two major negative regulators of mammalian target of 
      rapamycin (mTOR), leads to massive apoptotic cell death during EB development of 
      human AFS cells without affecting the endodermal, mesodermal and ectodermal cell 
      differentiation spectrum. Co-knockdown of endogenous mTOR demonstrated these 
      effects to be mTOR-dependent. Our findings prove this enzyme cascade to be an 
      essential anti-apoptotic gatekeeper of stem-cell differentiation during EB 
      formation. These data allow new insights into the regulation of early stem-cell 
      maintenance and differentiation and identify a new role of the tumor suppressor 
      tuberin and the oncogenic protein PRAS40 with the relevance for a more detailed 
      understanding of the pathogenesis of diseases associated with altered activities 
      of these gene products.
FAU - Fuchs, Christiane
AU  - Fuchs C
AD  - Institute of Medical Genetics, Medical University of Vienna, Wahringer Strasse 
      10, Vienna 1090, Austria.
FAU - Rosner, Margit
AU  - Rosner M
FAU - Dolznig, Helmut
AU  - Dolznig H
FAU - Mikula, Mario
AU  - Mikula M
FAU - Kramer, Nina
AU  - Kramer N
FAU - Hengstschlager, Markus
AU  - Hengstschlager M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111116
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (AKT1S1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Amniotic Fluid/*cytology
MH  - *Apoptosis
MH  - *Cell Differentiation
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Down-Regulation
MH  - Embryoid Bodies/cytology/physiology
MH  - Germ Layers/cytology
MH  - Humans
MH  - Pluripotent Stem Cells/*cytology/*physiology
MH  - RNA, Small Interfering
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/*metabolism
EDAT- 2011/11/18 06:00
MHDA- 2012/07/06 06:00
CRDT- 2011/11/18 06:00
PHST- 2011/11/18 06:00 [entrez]
PHST- 2011/11/18 06:00 [pubmed]
PHST- 2012/07/06 06:00 [medline]
AID - ddr535 [pii]
AID - 10.1093/hmg/ddr535 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2012 Mar 1;21(5):1049-61. doi: 10.1093/hmg/ddr535. Epub 2011 Nov 
      16.