Bonk, Ulrich
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Bonk, Ulrich
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Bonk, Ulrich
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Item-typ:Veröffentlichung, Identifizierung und Charakterisierung von Retrosequenzen der tumorrelevanten HMGA Gene im menschlichen Genom(2003-12-16); ; ; Retrosequences of protein-coding genes are generated by retrotransposition, i.e. reverse transcription of the genes´ mRNAs followed by integration into the genome. More than 8.000 genomic cDNA copies from an estimated total of 20.000 have been identified so far in human. Their biological relevance depends on the function of their respective (retrotranscribed) gene, on their own transcriptional status (active: retrogene / inactive: retropseudogene), but also on their integration site. The high mobility group protein (HMG) gene family is regarded as one of the largest retrosequence families in human. This thesis represents the first detailed study of retrosequences of a complete HMG group, i.e. HMGA. HMGA proteins play an important role in cell differentiation and tumorigenesis making possible active retrosequences of their genes interesting subjects. During the study 7 retrosequences of HMGA1 located on different chromosomes could be identified and characterised in detail concerning their formation, integration, transcriptional status and their possible role in tumorigenesis. They were derived from 5 different mRNA splice variants from which 2 have not been cloned yet. Their retrotransposition appeared to have been catalysed by the L1 endonuclease/reverse transcriptase ("target primed reverse transcription"). In silico analyses revealed 3 transcriptionally active retrosequences in normal and pathogenic tissues. At least one of them represents a new exon of an unknown gene. Concerning a possile relevance of the retrosequences for tumor initiation and / or progression 2 hypotheses were tested by analyzing chromosomal aberrations in cases of several solid benign tumor entities. The first hypothesis implied an own tumor-inducing potential of the retrosequences as proto-oncogenes. Whereas the second one suggested a mutational influence on the tumor-related HMGA genes by homologous recombination as aberration partners. Statistical analyses supported both hypotheses.Dissertation201 350 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Molekulargenetische Charakterisierung der Bruchpunktregion 19q13.4 bei gutartigen follikulären Schilddrüsentumoren und Charakterisierung des Kandidaten-Gens ZNF331(2004-08-25); ; ; The significance in the high incidence of thyroid nodules is that some of these nodules may harbour thyroid tumors. Still, the molecular mechanisms underlying the tumor formation are not fully understood. In this study, the positional cloning approach was used to characterize the chromosomal breakpoints specific for the two main cytogenetic subgroups in benign follicular thyroid tumors which habor chromosomal alterations in 19q13 and 2p21, respectively. In the cytogenetic subgroup with 19q13 aberrations, a candidate gene ZNF331 was identified at a 25 kbp distance proximal to the breakpoint region. ZNF331 consists of 15 exons and encodes for a 463 aa protein with a 42 aa KRAB-A domain and a 332 aa zinc finger region. The normal expression pattern of ZNF331 shows 3 transcripts of 2.1, 4.0 und 4.8 kbp. Exclusively in cell lines established from thyroid adenomas with 19q13 aberration, the expression of a 3.4 kbp transcript was detected. Hidden translocations involving chromosome 19 may mask a higher rate of clonal aberrations in benign thyroid tumors. FISH analyses did not confirm the existence of such translocations in a subset of 38 thyroid adenomas with apparently normal karyotype. The characterization of the canine orthologue of ZNF331 showed a high percentage of sequence identity with its human counterpart at the nucleic acid level as well as at the amino acid level. By FISH, canine ZNF331 was mapped to the terminal region of canine chromosome 1, i.e. CFA1q33.In the cytogenetic subgroup with 2p21 aberrations, a candidate gene, THADA, covering the 450-kbp breakpoint region was identified and first characterized. In two cell lines with 2p21 aberrations, the chromosomal breakpoint was narrowed down to intron 28 of THADA. Analyses of fusion transcripts resulting from the aberrations pointed to truncation of THADA rather than fusion to particular coding sequences as the critical effect of the chromosomal breaks.Dissertation205 93