Beitrag (Sammelband oder Tagungsband)
Bedingungen einer katholischen Moraltheologie in der Wissenschaft
Die Wissenschaftlichkeit der Theologie: Band 2: Katholische Disziplinen und ihre Wissenschaftstheorien (Studien zur systematischen Theologie, Ethik und Philosophie), Münster, vol. 13/2
L. Feuerer, S. Lamm, I. Henz, Melanie Kappelmann-Fenzl, S. Haferkamp, S. Meierjohann, C. Hellerbrand, S. Kuphal, A. Bosserhoff
Role of MIA (melanoma inhibitory activity) in melanocyte senescence
Pigment Cell & Melanoma Research, no. First Published: 06 June 2019
The protein MIA is known to be expressed in melanoma and to support melanoma progression. Interestingly, previous studies also observed the expression of MIA in nevi. Concentrating on these findings, we revealed that MIA expression is correlated with a senescent state in melanocytes. Induction of replicative or oncogene‐induced senescence resulted in increased MIA expression in vitro. Notably, MIA‐knockdown in senescent melanocytes reduced the percentage of senescence‐associated beta‐Gal‐positive cells and enhanced proliferation. Using the melanoma mouse model Tg(Grm1), MIA‐deficient mice supported the impact of MIA on senescence by showing a significantly earlier tumor onset compared to controls. In melanocytes, MIA‐knockdown led to a downregulation of the cell cycle inhibitor p21 in vitro and in vivo. In contrast, after induction of hTERT in human melanoma cells, p21 regulation by MIA was lost. In summary, our data show for the first time that MIA is a regulator of cellular senescence in human and murine melanocytes.
Beitrag (Sammelband oder Tagungsband)
Stephan Gronwald, D. Melchart
Entwicklung und Erprobung eines Bio-Psycho-Sozialen Analyseinstrumentes zur Identifizierung von Belastungen im Handwerk
Institut für Betriebliches Gesundheitsmanagement und Arbeitssicherheit
Forschungsbericht 2016/2017 der Technischen Hochschule Deggendorf
B. Spangler, Melanie Kappelmann-Fenzl, B. Schittek, S. Meierjohann, L. Vardimon, A. Bosserhoff, S. Kuphal
ETS‐1/RhoC signaling regulates the transcription factor c‐Jun in melanoma
International Journal of Cancer, vol. 130, no. 12, pp. 2801-2811
Recently, we discovered that the loss of E‐cadherin induces c‐Jun protein expression, which is a member of the AP‐1 transcription factor family and a key player in the processes of cell proliferation and tumor development and also found in elevated levels in melanomas. Notably, the mRNA level of c‐Jun was not affected, suggesting that c‐Jun is regulated at post‐transcriptional level. Here, we present data that suggest that the dynamic cytoskeletal network, linked to E‐cadherin, is involved in the regulation of the c‐Jun protein and transcriptional activity. In a signaling cascade, the loss of E‐cadherin activates the transcriptional regulator ETS‐1 and consequently leads to the induction of RhoC expression that stabilizes c‐Jun in melanoma. The link between RhoC and c‐Jun seems to be indirect via the cytoskeleton. We conclude that the loss of E‐cadherin mediated cell‐adhesion induces c‐Jun protein expression in a multistep process, offering several possibilities for therapeutic intervention.
Melanie Kappelmann-Fenzl, S. Kuphal, G. Meister, L. Vardimon, A. Bosserhoff
MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression
Oncogene, vol. 32, no. 24, pp. 2984-2991
A fundamental event in the development and progression of malignant melanoma is the deregulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of tumor progression in melanoma and thus the most important member of the AP-1 transcription factor family for this disease. Interestingly, we revealed that c-Jun expression was regulated on the post-transcriptional level and therefore speculated that miRNAs could be involved in c-Jun regulation. We determined seed sequences for miR-125b and miR-527 in the coding region of c-Jun mRNA that hints at the direct involvement of miRNA-dependent regulation on the protein level. We found that the expression of miR-125b was significantly reduced in malignant melanoma cell lines and tissue samples compared with melanocytes, whereas miR-527 remained unchanged. In further functional experiments, treatment of melanoma cells with pre-miR-125b resulted in strong suppression of cellular proliferation and migration, supporting the role of miR-125b in melanoma. In addition, transfection of pre-miR-125b led to strong downregulation of c-Jun protein but not mRNA expression in melanoma cells. Luciferase assays using reporter plasmids containing the miR-125b seed sequence in the luciferase coding region confirmed the direct interaction with miR-125b. Furthermore, immunoprecipitation of Ago-2 revealed that c-Jun mRNA accumulated in the RNA-induced silencing complex after pre-miR-125b transfection in melanoma cells. In summary, we identified an important role for miR-125b in malignant melanoma. Moreover, we demonstrated post-transcriptional regulation of c-Jun by this miRNA and showed that c-Jun is a main mediator of the effects of miR-125b on melanoma cells.
P. Schummer, S. Kuphal, L. Vardimon, A. Bosserhoff, Melanie Kappelmann-Fenzl
Specific c-Jun target genes in malignant melanoma
Cancer Biology & Therapy, vol. 17, no. 5, pp. 486-497
A fundamental event in the development and progression of malignant melanoma is the de-regulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of melanoma progression and, thus, is the most important member of the AP-1 transcription factor family in this disease. Surprisingly, no cancer-related specific c-Jun target genes in melanoma were described in the literature, so far. Therefore, we focused on pre-existing ChIP-Seq data (Encyclopedia of DNA Elements) of 3 different non-melanoma cell lines to screen direct c-Jun target genes. Here, a specific c-Jun antibody to immunoprecipitate the associated promoter DNA was used. Consequently, we identified 44 direct c-Jun targets and a detailed analysis of 6 selected genes confirmed their deregulation in malignant melanoma. The identified genes were differentially regulated comparing 4 melanoma cell lines and normal human melanocytes and we confirmed their c-Jun dependency. Direct interaction between c-Jun and the promoter/enhancer regions of the identified genes was confirmed by us via ChIP experiments. Interestingly, we revealed that the direct regulation of target gene expression via c-Jun can be independent of the existence of the classical AP-1 (5´-TGA(C/G)TCA-3´) consensus sequence allowing for the subsequent down- or up-regulation of the expression of these cancer-relevant genes. In summary, the results of this study indicate that c-Jun plays a crucial role in the development and progression of malignant melanoma via direct regulation of cancer-relevant target genes and that inhibition of direct c-Jun targets through inhibition of c-Jun is a potential novel therapeutic option for treatment of malignant melanoma.