dc.contributor.author
Snarski, Emilian
dc.date.accessioned
2018-06-07T17:08:47Z
dc.date.available
2005-11-09T00:00:00.649Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/3467
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-7667
dc.description.abstract
The Wilms Tumor gene 1 codes a powerful transcription factor that appears to
play a pivotal role in the regulation of cell proliferation and
differentiation. The physiological expression of WT1 is restricted to a few
types of developing tissues: blood precursor cells, kidney precursors and
cells in the mammary ducts. The abnormal expression of WT1 had been found in
various human neoplasias. WT1 expressed in neoplasias lacks mutations and
reduction of its expression blocks proliferation and leads to apoptosis or
cell differentiation. There are few possible causes that could explain the
abnormal expression of WT1: the gene could be mutated, which could lead to
constitutive expression, an abnormal expression of physiological activators
could activate WT1 expression, and an epigenetic modification of DNA could
activate WT1. All three possible causes for pathological upregulation of WT1
gene were investigated in this work. The genes PAX2, PAX8 and GATA1 are
physiological activators and regulators of WT1 expression. The expression
patterns of these genes were analyzed in carcinoma cell lines and human
carcinoma tissue samples. A close correlation was observed between expression
of WT1 and PAX2 and PAX8. However, the correlation was not linear but rather
of a threshold type. WT1 expression appeared when activators where expressed
at certain levels. A model of an on off regulation is proposed in which
the expression of an activator had to reach certain level (termed activation
threshold) to activate expression of WT1. The method of RNA interference was
used to further analyze the interactions between WT1 and activator genes. The
genes WT1, GATA1, PAX2 and PAX8 were silenced in a series of experiments. It
was shown that RNAi reduce the growth in WT1 expressing cells by 50%. However,
the reduction of WT1 expression achieved with RNAi did not lead to an increase
in apoptosis. Targeting of each of the regulator genes caused similar effects
downregulation of the activator was followed first by downregulation of WT1
and later by downregulation of housekeeping genes. When the WT1 regulators
were targeted the relative downregulation of WT1 was lower than in the case of
direct targeting. When regulators were downregulated also the growth reduction
was less pronounced than in cases with direct targeting of WT1. Taken
together, it can be implied that WT1 is regulated by PAX2, PAX8 and GATA1.
de
dc.description.abstract
Die Arbeit beschreibt Aspekte der Expressionsregulation vom Wilms Tumor Gen
1(WT1) bei humanen Neoplasien. Die Hauptregulatoren sind die Gene PAX2, PAX8
und GATA1. Die Experimente bezueglich RNA Interferenz zeigen den Zusammenhang
zwischen der Expression von PAX2, PAX8, GATA1 und WT1. Mutationen im WT1-Gen
und in den Promotoren von PAX2, PAX8 und GATA1 spielen keine Rolle bei WT1
Tumorexpression. Die Methylierung von WT1 Enhancer ist dagegen ein wichtiger
Faktor.
de
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject
Wilms Tumor Gene PAX2 PAX8 GATA1
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Regulation of Wilms Tumor Gene 1 (WT1) expression
dc.contributor.firstReferee
Prof. Dr. med. U. Keilholz
dc.contributor.furtherReferee
Prof. Dr. med. Dr. h. c. G. Henze
dc.date.accepted
2005-11-08
dc.date.embargoEnd
2005-11-09
dc.identifier.urn
urn:nbn:de:kobv:188-2005002996
dc.title.translated
Expressionsregulation von Wilms Tumor Gen 1 (WT1) bei humanen Neoplasien
de
refubium.affiliation
Charité - Universitätsmedizin Berlin
de
refubium.mycore.fudocsId
FUDISS_thesis_000000001827
refubium.mycore.transfer
http://www.diss.fu-berlin.de/2005/299/
refubium.mycore.derivateId
FUDISS_derivate_000000001827
dcterms.accessRights.dnb
free
dcterms.accessRights.openaire
open access