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|Nachweis von Mutationen im Gen des NfkappaB-Inhibitors alpha in kultivierten und primären Tumorzellen des Hodgkin Lymphoms|
|Main title||Nachweis von Mutationen im Gen des NfkappaB-Inhibitors alpha in kultivierten und primären Tumorzellen des Hodgkin Lymphoms|
|Title variations||Mutations in the nfkappaB inhibitor gen IkappaBalpha in cultivated and primary tumor cells of hodgkin lymphoma|
Place of birth: Saarbruecken, Deutschland
|1. Referee||Prof. Dr. Bernd Dörken|
|Further Referee(s)||Prof. Dr. Lorenz Trümper
Prof. Dr. Alfred C. Feller
|Keywords||IkappaB, Hodgkin lymphoma, mutation, NfkappaB, single cell PCR|
|Classification (DDC)||610 Medical sciences; Medicine|
|Summary||The Hodgkin Lymphoma is one of the most common lympho-proliferative disorders in industrialized countries. Although significant therapeutical progress has been achieved in the past, the molecular mechanisms of the tumor development still remain unclear.
Previous studies have shown that the transcription factor NfkappaB is constitutively active in Hodgkin and Reed-Sternberg (HRS)-cells, the actual tumor cells of the Hodgkin lymphoma. This leads to an unregulated activation of many target genes that are involved in the regulation of apoptosis, the control of cell-growth, differentiation and activation.
The transcriptional activity of NfkappaB within the cell-nucleus is predominantly regulated by inhibitors (IkappaB) that bind NfkappaB in the cytoplasm. The inhibitor IkappaBalpha, whose expression is regulated in turn by NfkappaB through a negative feedback-mechanism, plays a central role in the inhibition of NfkappaB function.
The main objective of this study was to investigate, whether genetic defects of IkappaBalphaare responsible for constitutive NfkappaB activity.
First, the IkappaBalpha gene, its mRNA and protein was analyzed in cell-lines derived from Hodgkin lymphomas. Two out of six cell-lines showed mutations that lead to truncated versions of the IkappaBalpha protein that are no longer capable of binding and inhibiting NfkappaB. Next, to examine whether similar mutations also occur in primary HRS-cells, the IkappaBalpha gene in 420 single HRS-cells of 10 Hodgkin cases was analyzed by a two-step single copy PCR. One case showed a premature stop-codon that also leads to a truncated version of the protein.
Finally, the expression level of the IkappaBalpha mRNA was evaluated through in-situ hybridization experiments of 20 primary Hodkgin samples. In the vast majority of these cases a significant over-expression of IkappaBalpha was detected. This observation confirms the correlation between highly active NfkappaB and up-regulation of IkappaBalpha through intracellular regulatory mechanisms, but without causing a sufficient inhibition of NfkappaB in Hodgkin’s´lymphoma.
These results show, that he constitutive activity of NfkappaB in HRS-cells can be partly explained by defects in the IkappaBalpha gene. However, in the majority of Hodgkin lymphomas other factors and mechanisms cause the unrestricted activity of NfkappaB. It remains a challenge for future research to identify these factors.
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|FU Department||Department of Medicine - Charité - University Medicine Berlin|
|Year of publication||2006|
|Document type||Doctoral thesis|
|Date of defense||2006-06-23|
|Created at||2006-05-26 : 12:00:00|
|Last changed||2010-02-19 : 11:07:32|
|Old Darwin URL||http://www.diss.fu-berlin.de/2006/316/|