TY  - JOUR
A1  - Wiegering, Armin
A1  - Pfann, Christina
A1  - Uthe, Friedrich Wilhelm
A1  - Otto, Christoph
A1  - Rycak, Lukas
A1  - Mäder, Uwe
A1  - Gasser, Martin
A1  - Waaga-Gasser, Anna-Maria
A1  - Eilers, Martin
A1  - Germer, Christoph-Thomas
T1  - CIP2A Influences Survival in Colon Cancer and Is Critical for Maintaining Myc Expression
JF  - PLoS ONE
N2  - The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor that stabilises the c-Myc protein. CIP2A is overexpressed in several tumours, and expression levels are an independent marker for long-term outcome. To determine whether CIP2A expression is elevated in colon cancer and whether it might serve as a prognostic marker for survival, we analysed CIP2A mRNA expression by real-time PCR in 104 colon cancer samples. CIP2A mRNA was overexpressed in colon cancer samples and CIP2A expression levels correlated significantly with tumour stage. We found that CIP2A serves as an independent prognostic marker for disease-free and overall survival. Further, we investigated CIP2A-dependent effects on levels of c-Myc, Akt and on cell proliferation in three colon cancer cell lines by silencing CIP2A using small interfering (si) and short hairpin (sh) RNAs. Depletion of CIP2A substantially inhibited growth of colon cell lines and reduced c-Myc levels without affecting expression or function of the upstream regulatory kinase, Akt. Expression of CIP2A was found to be dependent on MAPK activity, linking elevated c-Myc expression to deregulated signal transduction in colon cancer.
KW  - caco-2 cells
KW  - carcinomas
KW  - colon
KW  - colorectal cancer
KW  - MAPK signaling cascades
KW  - metastasis
KW  - protein expression
KW  - small interferring RNA
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97252
ER  - 
TY  - JOUR
A1  - Kim, Mia
A1  - Grimmig, Tanja
A1  - Grimm, Martin
A1  - Lazariotou, Maria
A1  - Meier, Eva
A1  - Rosenwald, Andreas
A1  - Tsaur, Igor
A1  - Blaheta, Roman
A1  - Heemann, Uwe
A1  - Germer, Christoph-Thomas
A1  - Waaga-Gasser, Ana Maria
A1  - Gasser, Martin
T1  - Expression of Foxp3 in Colorectal Cancer but Not in Treg Cells Correlates with Disease Progression in Patients with Colorectal Cancer
JF  - PLoS ONE
N2  - Background
Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA.

Hypothesis
Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing.

Methods
To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression.

Results
Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry.

Conclusions
PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
KW  - T cells
KW  - gene regulation
KW  - alternative splicing
KW  - measles virus
KW  - T cell receptors
KW  - reverse transcriptase-polymerase chain reaction
KW  - TCR signaling cascade
KW  - cell cycle and cell division
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130340
VL  - 8
IS  - 1
ER  -