Control of growth and differentiation of human neuronal and hematopoietic tumour cells via Myc/Max/Mad-network proteins

摘要: The Myc/Max/Mad transcription factor network regulates a large number of genes involved in cell growth, differentiation and apoptosis. Myc activates Mad represses overlapping set growth-promoting genes, the therefore seems to act as molecular switch between growth differentiation. Deregulation myc–family occurs frequently human cancers is often associated with poor prognosis. One aim this thesis was identify negative signals affecting expression and/or activity N-Myc- Mad-family neuroblastomas. Our results show that Mad1 upregulated during phorbol ester (TPA)-induced neuronal SH-SY5Y neuroblastoma cells lacking N-myc amplification, whereas response largely inhibited N-myc-amplified cells. However, interferon-γ (IFN-γ) combination retinoic acid (RA) or TPA strongly enhanced arrest latter. This accompanied by reduced N-Myc expression, resulting changed occupancy at ODC target gene promoter vivo towards Mad1/Max predominance, repression N-Myc/Mad1 genes. suggests combined RA+IFN-γ “differentiation therapy” may potentially be clinical interest treatment. Addressing role hematopoietic differentiation, we enforced U-937 monoblasts an inducible system led proliferation. did not induce enhance absence presence signals. Surprisingly, stimulated TNF-α-, but Fas-induced apoptosis Finally, addressing still unclear mechanism which c-Myc transcription, our showed differentiation-induced cyclin-dependent kinase inhibitor p21Cip1 repressed through interaction Zn-finger protein Miz-1 p21 core promoter. function from activator repressor, thereby inhibiting cycle exit