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@ARTICLE{Jeibmann:120468,
author = {A. Jeibmann and J. Schulz and K. Eikmeier and P. Johann$^*$
and K. Thiel and I. Tegeder and O. Ambrée and M. C.
Frühwald and S. Pfister$^*$ and M. Kool$^*$ and W. Paulus
and M. Hasselblatt},
title = {{SMAD} dependent signaling plays a detrimental role in a
fly model of {SMARCB}1-deficiency and the biology of
atypical teratoid/rhabdoid tumors.},
journal = {Journal of neuro-oncology},
volume = {131},
number = {3},
issn = {1573-7373},
address = {Dordrecht [u.a.]},
publisher = {Springer Science + Business Media B.V},
reportid = {DKFZ-2017-00897},
pages = {477 - 484},
year = {2017},
abstract = {Atypical teratoid/rhabdoid tumors (ATRT) are highly
malignant brain tumors arising in young children. The
majority of ATRT is characterized by inactivation of the
chromatin remodeling complex member SMARCB1 (INI1/hSNF5).
Little is known, however, on downstream pathways involved in
the detrimental effects of SMARCB1 deficiency which might
also represent targets for treatment. Using Drosophila
melanogaster and the Gal4-UAS system, modifier screens were
performed in order to identify the role of SMAD dependent
signaling in the lethal phenotype associated with knockdown
of snr1, the fly homolog of SMARCB1. Expression and
functional role of human homologs was next investigated in
ATRT tumor samples and SMARCB1-deficient rhabdoid tumor
cells. The lethal phenotype associated with snr1 knockdown
in Drosophila melanogaster could be shifted to later stages
of development upon additional knockdown of several
decapentaplegic pathway members including Smox, and Med.
Similarly, the transforming growth factor beta (TGFbeta)
receptor type I kinase inhibitor SB431542 ameliorated the
detrimental effect of snr1 knockdown in the fruit fly.
Examination of homologs of candidate decapentaplegic pathway
members in human SMARCB1-deficent ATRT samples revealed
SMAD3 and SMAD6 to be over-expressed. In SMARCB1-deficent
rhabdoid tumor cells, siRNA-mediated silencing of SMAD3 or
SMAD6 expression reduced TGFbeta signaling activity and
resulted in decreased proliferation. Similar results were
obtained upon pharmacological inhibition of TGFbeta
signaling using SB431542. Our data suggest that SMAD
dependent signaling is involved in the detrimental effects
of SMARCB1-deficiency and provide a rationale for the
investigation of TGFbeta targeted treatments in ATRT.},
cin = {B062 / L101},
ddc = {610},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:28108836},
doi = {10.1007/s11060-016-2326-3},
url = {https://inrepo02.dkfz.de/record/120468},
}