Subject(s)
Factor VIII/analysis , Hemophilia A/pathology , Chromogenic Compounds/chemistry , Chromogenic Compounds/metabolism , DNA/analysis , DNA/isolation & purification , Enzyme Assays , Factor VIII/genetics , Genotype , Hemophilia A/genetics , Humans , Partial Thromboplastin Time , Phenotype , Polymorphism, Genetic , Sequence Analysis, DNA , Severity of Illness IndexABSTRACT
The CCAAT/enhancer-binding protein alpha, encoded by the intronless CEBPA gene, is a transcription factor that induces expression of genes involved in differentiation of granulocytes, monocytes, adipocytes and hepatocytes. Both mono- and bi-allelic CEBPA mutations were detected in acute myeloid leukaemia and myelodysplastic syndrome. In this study we also identified CEBPA mutations in healthy individuals and in patients with peripheral artery disease, ischaemic heart disease and hyperlipidaemia. We found 16 various deletions with the presence of two direct repeats in CEBPA by analysis of 431 individuals. Three most frequent repeats included in these deletions in CEBPA gene are CGCGAG (493- 498_865-870), GG (486-487_885-886), and GCCAAGCAGC (508-517_907-916), all according to GenBank Accession No. NM_004364.2. In one case we identified that a father with ischaemic heart disease and his healthy son had two identical deletions (493_864del and 508_906del, both according to GenBank Accession No. NM_004364.2) in CEBPA. The occurrence of deletions between two repetitive sequences may be caused by recombination events in the repair process. A double-stranded cut in DNA may initiate these recombination events in adjacent DNA sequences. Four types of polymorphisms in the CEBPA gene were also detected in the screened individuals. Polymorphism in CEBPA gene 690 G>T according to GenBank Accession No. NM_004364.2 is the most frequent type in our analysis. Statistical analysis did not find significant differences in the frequency of polymorphisms in CEBPA in patients and in healthy individuals with the exception of P4 polymorphism (580_585dup according to GenBank Accesion No. NM_004364.2). P4 polymorphism was significantly increased in ischaemic heart disease patients.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/genetics , Hyperlipidemias/genetics , Mutation , Myocardial Ischemia/genetics , Peripheral Vascular Diseases/genetics , Polymorphism, Genetic , Amino Acid Sequence , Base Sequence , CCAAT-Enhancer-Binding Protein-alpha/metabolism , DNA Mutational Analysis , Humans , Molecular Sequence DataABSTRACT
Chromosome translocations are detected in 50-70% of human leukaemia. The promyelocytic leukaemia (PML) gene is involved in the t(15;17) chromosomal translocation of acute promyelocytic leukaemia (APL). PML gene encodes a protein, which was shown to be concentrated in PML-nuclear bodies. Histone acetyltransferases and deacetylases, and chromatin-modifying proteins are accumulated in complexes with PML protein in these nuclear bodies giving the evidence of their role in transcription regulation. Physical interactions of PML protein with transcription factors, co-activators and co-repressors of transcription correspond with the role of PML in transcription regulation. PML plays an important role in apoptosis, proliferation and senescence of cells. PML gene is a tumour-suppressor gene and a product of its expression acts as a potent cell growth suppressor. All these activities of PML protein are ascribed to its nuclear functions. Cytoplasmic form of PML (cPML) is also very important and it is critical for transforming growth factor-beta (TGF-beta) signalling. Cytoplasmic PML interacts with two TGF-beta receptors (TbetaBRI and TbetaRII) and acts as a bridging factor between protein called Smad anchor of receptor activation (SARA) and Smad proteins and it plays a role in the transport of whole complex into the early endosomes in TGF-beta signalling. The loss of functional cPML induces not only APL but it might influence behaviour of cancer cells and their resistance to TGF-beta.
