Abstract
FA (Fanconi anaemia) is a rare hereditary disorder characterized by congenital malformations, progressive bone marrow failure and an extraordinary predisposition to develop cancer. At present, 15 genes have been related to this condition and mutations of them have also been found in different types of cancer. Bone marrow failure threatens the life of FA patients during the first decade of their life, but the mechanisms underlying this process are not completely understood. In the present study we investigate a possible imbalance between the expression of pro- and anti-apoptotic proteins as a cause for the hypersensitivity of FANCC (FA, complementation group C)-deficient cells to genotoxic stress. We found a BIK (Bcl-2 interacting killer) over-expression in lymphoblastoid cell lines derived from FA-C patients when compared with their phenotypically corrected counterparts. This overexpression has a transcriptional basis since the regulatory region of the gene shows higher activity in FANCC-deficient cells. We demonstrate the involvement of BIK in the sensitivity of FA-C lymphoblasts to interstrand DNA cross-linking agents as it is induced by these drugs and interference of its expression in these cells preserves their viability and reduces apoptosis. We investigate the mechanism of BIK overexpression in FANCC-deficient cells by analysing the activity of many different signalling pathways in these cells. Finally, we provide evidence of a previously undescribed indirect epigenetic regulation of BIK in FA-C lymphoblasts mediated by ΔNp73, an isoform of p73 lacking its transactivation domain that activates BIK through a proximal element in its promoter.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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5' Untranslated Regions
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / physiology*
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Cell Line
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Cell Line, Transformed
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Cisplatin / pharmacology
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Cross-Linking Reagents / pharmacology
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DNA / drug effects
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DNA Damage*
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DNA Methylation
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DNA-Binding Proteins / physiology*
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Fanconi Anemia / genetics
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Fanconi Anemia / metabolism
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Fanconi Anemia / pathology*
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Fanconi Anemia Complementation Group C Protein / deficiency
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Fanconi Anemia Complementation Group C Protein / genetics
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Fanconi Anemia Complementation Group C Protein / physiology
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Genes, Reporter
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Humans
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Lymphocytes / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Mitochondrial Proteins
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Mitomycin / pharmacology
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Nuclear Proteins / physiology*
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Promoter Regions, Genetic
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Transcriptional Activation
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Tumor Protein p73
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Tumor Suppressor Proteins / physiology*
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bcl-2-Associated X Protein / biosynthesis
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bcl-2-Associated X Protein / genetics
Substances
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5' Untranslated Regions
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Apoptosis Regulatory Proteins
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BAX protein, human
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BBC3 protein, human
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BIK protein, human
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Cross-Linking Reagents
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DNA-Binding Proteins
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FANCC protein, human
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Fanconi Anemia Complementation Group C Protein
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Membrane Proteins
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Mitochondrial Proteins
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Nuclear Proteins
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PMAIP1 protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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TP73 protein, human
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Tumor Protein p73
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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delta Np73 protein, human
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Mitomycin
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DNA
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Cisplatin