Neuroblastoma-derived sulfhydryl oxidase, a new member of the sulfhydryl oxidase/Quiescin6 family, regulates sensitization to interferon gamma-induced cell death in human neuroblastoma cells.
In neuroblastoma cells, apoptotic programs can be activated by cytokines and cytostatic drugs. Apoptotic dysfunction confers resistance against therapeutic drugs and is a major complication for achieving optimal therapy response. Deregulated expression of the MYCN gene is a critical determinant in neuroblastoma progression, and one of the pleiotropic functions of the MYCN protein is cellular sensitization to cytokine-induced and drug-induced apoptosis. By using the functional approach of technical knockout (TKO), we have identified five genes that regulate sensitization for IFN-gamma-induced cell death. Most efficient among them is the newly identified SOXN (neuroblastoma-derived sulfhydryl oxidase), which comprises 12 exons and maps to 9q34.3. SOXN encodes a putative protein of 698 amino acids that contains a signal sequence, a protein-disulfide-isomerase-type thioredoxin and a yeast ERV1 domain and is highly homologous to members of the sulfhydryl oxidase/Quiescin6 family. The SOXN protein is predominantly located in the plasma and in the nuclear membrane. Antisense SOXN confers resistance to IFN-gamma-induced apoptosis. In contrast, ectopic overexpression of sense-SOXN sensitizes the cells to induced cell death. These results identify SOXN as a major player in regulating the sensitization of neuroblastoma cells for IFN-gamma-induced apoptosis.
Wittke
Isabel
I
Department of Tumor Genetics (B030), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Wiedemeyer
Ruprecht
R
Pillmann
Andrea
A
Savelyeva
Larissa
L
Westermann
Frank
F
Schwab
Manfred
M
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002462:Cell Membrane / Q000201:enzymology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D016373:DNA, Antisense / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D016373:DNA, Antisense; D018076:DNA, Complementary; D007371:Interferon-gamma; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; D012333:RNA, Messenger; C481160:QSOX2 protein, human