Leucine-zipper protein, LDOC1, inhibits NF-kappaB activation and sensitizes pancreatic cancer cells to apoptosis.
We have isolated a novel gene, LDOC1, which encodes for a leucine zipper protein that was downregulated in a series of human pancreatic cancer cell lines but was expressed in corresponding normal tissues. We report the initial characterization of LDOC1 as a novel regulator of the transcriptional response mediated by the nuclear factor kappa B (NF-kappaB). Transient expression of LDOC1 significantly inhibited the luciferase activity in LDOC1-negative BxPC-3 pancreatic cancer cell line transfected with the NF-kappaB reporter plasmid, activated with mitogen-activated protein kinase/ERK kinase kinase-1 (MEEK). LDOC1, however, does not affect p53, AP1 and CRE-dependent reporter gene expression. The activation of NF-kappaB through ligand-induced stimulation by tumor necrosis factor-alpha (TNF-alpha) or phorbol 12-myristate 13-acetate (PMA) was also inhibited by transient expression of LDOC1 in a dose dependent manner. To determine the growth effect of LDOC1 expression on cancer cells, BxPC-3 cells were stably transfected with LDOC1 cDNA. Viability studies demonstrated that TNF-alpha or PMA-induced antiproliferative effects were significantly enhanced by stable transfection of cells with LDOC1. These observations suggest that LDOC1 is a novel regulator of NF-kappaB that can affect the PMA or TNF-alpha-mediated pathway to apoptosis through inhibition of NF-kappaB activation in BxPC3 pancreatic cancer cells.
Nagasaki
Koichi
K
Department of Obstetrics and Gynecology, University of Kiel, Kiel, Germany. knagasaki@email.uni-kiel.de
Schem
Christian
C
von Kaisenberg
Constantin
C
Biallek
Marco
M
Rösel
Frank
F
Jonat
Walter
W
Maass
Nicolai
N
D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
C120625:LDOC1 protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D013755:Tetradecanoylphorbol Acetate