TY  - JOUR
A1  - Unterberg, Marlies
A1  - Leffers, Larissa
A1  - Hübner, Florian
A1  - Humpf, Hans-Ulrich
A1  - Lepikhov, Konstantin
A1  - Walter, Jörn
A1  - Ebert, Franziska
A1  - Schwerdtle, Tanja
T1  - Toxicity of arsenite and thio-DMAV after long-term (21 days) incubation of human urothelial cells: cytotoxicity, genotoxicity and epigenetics
JF  - Toxicology Research
N2  - This study aims to further mechanistically understand toxic modes of action after chronic inorganic arsenic exposure. Therefore long-term incubation studies in cultured cells were carried out, to display chronically attained changes, which cannot be observed in the generally applied in vitro short-term incubation studies. Particularly, the cytotoxic, genotoxic and epigenetic effects of an up to 21 days incubation of human urothelial (UROtsa) cells with pico- to nanomolar concentrations of iAsIII and its metabolite thio-DMAV were compared. After 21 days of incubation, cytotoxic effects were strongly enhanced in the case of iAsIII and might partly be due to glutathione depletion and genotoxic effects on the chromosomal level. These results are in strong contrast to cells exposed to thio-DMAV. Thus, cells seemed to be able to adapt to this arsenical, as indicated among others by an increase in the cellular glutathione level. Most interestingly, picomolar concentrations of both iAsIII and thio-DMAV caused global DNA hypomethylation in UROtsa cells, which was quantified in parallel by 5-medC immunostaining and a newly established, reliable, high resolution mass spectrometry (HRMS)-based test system. This is the first time that epigenetic effects are reported for thio-DMAV; iAsIII induced epigenetic effects occur in at least 8000 fold lower concentrations as reported in vitro before. The fact that both arsenicals cause DNA hypomethylation at really low, exposure-relevant concentrations in human urothelial cells suggests that this epigenetic effect might contribute to inorganic arsenic induced carcinogenicity, which for sure has to be further investigated in future studies.
KW  - induced malignant-transformation
KW  - genomic dna methylation
KW  - vitro toxicological characterization
KW  - thio-dimethylarsinic acid
KW  - bladder-cancer
KW  - methyltransferases dnmt3a
KW  - cytosine methylation
KW  - carcinogen exposure
KW  - mass-spectrometry
KW  - gene-expression
Y1  - 2014
SN  - 2045-4538
SN  - 2045-452X
VL  - 3
IS  - 6
SP  - 456
EP  - 464
PB  - Royal Society of Chemistry
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Hammes, Annette
A1  - Andreassen, Thomas K.
A1  - Spoelgen, Robert
A1  - Raila, Jens
A1  - Hubner, Norbert
A1  - Schulz, Herbert
A1  - Metzger, Jochen
A1  - Schweigert, Florian J.
A1  - Luppa, Peter B.
A1  - Nykjaer, Andreas
A1  - Willnow, Thomas E.
T1  - Role of endocytosis in cellular uptake of sex steroids
N2  - Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs
Y1  - 2005
SN  - 0092-8674
ER  - 
TY  - JOUR
A1  - Schlag, Peter M.
A1  - Osterziel, Karl Joseph
A1  - Özcelik, Cemil
A1  - Scherneck, Siegfried
A1  - Wenzel, Katrin
A1  - Daskalow, Katjana
A1  - Herse, Florian
A1  - Seitz, Susanne
A1  - Zacharias, Ute
A1  - Schenk, Jörg A.
A1  - Schulz, Herbert
A1  - Hübner, Norbert
A1  - Micheel, Burkhard
T1  - The protein phosphatase 1 inhibitor KEPI is down regulated in breast cancer cell lines and tissues and involved in the regulation of the tumour suppressor EGR1 via the MEK-ERK pathway
N2  - KEPI is a protein kinase C-potentiated inhibitory protein for type 1 Ser/Thr protein phosphatases. We found no or reduced expression of KEPI in breast cancer cell lines, breast tumors and metastases in comparison to normal breast cell lines and tissues, respectively. KEPI protein expression and ubiquitous localization was detected with a newly generated antibody. Ectopic KEPI expression in MCF7 breast cancer cells induced differential expression of 95 genes, including the up-regulation of the tumor suppressors EGR1 (early growth response 1) and PTEN (phosphatase and tensin homolog), which is regulated by EGR1. We further show that the up-regulation of EGR1 in MCF7/KEPI cells is mediated by MEK-ERK signaling. The inhibition of this pathway by the MEK inhibitor UO126 led to a strong decrease in EGR1 expression in MCF7/KEPI cells. These results reveal a novel role for KEPI in the regulation of the tumor suppressor gene EGR1 via activation of the MEK-ERK MAPK pathway.
Y1  - 2008
UR  - http://www.atypon-link.com/doi/abs/10.1515/BC.2007.062
ER  -