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Susanne Voelter-Mahlknecht

Publications and source records attributed to Susanne Voelter-Mahlknecht.

11 recordsLinked to original sources
PubMed2006

Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1.

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which belongs to the silent information regulator 2 (Sir2) family of sirtuin histone deacetylases (HDACs). The yeast Sir2 protein and its mammalian derivatives play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging. We have isolated and characterized the human Sirt1 genomic sequence, which spans a region of 33,660 bp and which has one single genomic locus. Determination of the exon-intron splice junctions established that SIRT1 is encoded by 9 exons ranging in size from 80 bp (exon 6) to 2,120 bp (exon 9). Characterization of the 5' flanking genomic region, which precedes the Sirt1 open reading frame, revealed a CCAAT-box and a number of NF-kappaB and GATA transcription factor binding sites in addition to a small 350 bp CpG island. The 4,107 bp human Sirt1 mRNA has an open reading frame of 2,244 bp and encodes a 747 aa protein with a predictive molecular weight of 81.7 kDa and an isoelectric point of 4.55. Fluorescence in situ hybridization analysis localized the human Sirt1 gene to chromosome 10q21.3.

Amino Acid Sequence↗
PubMed2006

Chromosomal organization and fluorescence in situ hybridization of the human Sirtuin 6 gene.

Sirtuin 6 (SIRT6) is a member of the sirtuin deacetylases (sirtuins), which are derivatives of the yeast Silent information regulator 2 (Sir2) protein. SIR2 and its mammalian derivatives play a central role in epigenetic gene silencing, recombination, metabolism, cell differentiation and in the regulation of aging. In contrast to most sirtuins, SIRT6 lacks NAD+-dependent protein deacetylase activity. We have isolated and characterized the human Sirt6 genomic sequence, which spans a region of 8,427 bp and which has one single genomic locus. Determination of the exon-intron splice junctions found the full-length SIRT6 protein to consist of 8 exons ranging in size from 60 bp (exon 4) to 838 bp (exon 8). The human Sirt6 open reading frame encodes a 355-aa protein with a predictive molecular weight of 39.1 kDa and an isoelectric point of 9.12. Characterization of the 5' flanking genomic region, which precedes the Sirt6 open reading frame, revealed a TATA- and CCAAT-box less promoter with an approximately 300-bp long CpG island. A number of AML-1 and GATA-x transcription factor binding sites were found which remain to be further evaluated experimentally. Fluorescence in situ hybridization analysis localized the human Sirt6 gene to chromosome 19p13.3; a region which is frequently affected by chromosomal alterations in acute leukemia. Human SIRT6 appears to be most predominantly expressed in bone cells and in the ovaries while, in the bone marrow, it is practically absent. The functional characteristics of SIRT6 are essentially unknown at present and remain to be elucidated.

Alu Elements↗
PubMed2006

Fluorescence in situ hybridization and chromosomal organization of the human Sirtuin 7 gene.

Sirtuin 7 (SIRT7) is a member of the sirtuin family of protein deacetylases and is, therefore, a derivative of yeast Silent information regulator 2 (SIR2). SIR2 and its mammalian orthologs play an important role in epigenetic gene silencing, DNA recombination, cellular differentiation and metabolism, and the regulation of aging. In contrast to most sirtuins, SIRT7 does not exert characteristic NAD+-dependent deacetylase activity. We have isolated and characterized the human Sirt7 genomic sequence, which spans a region of 6.2 kb and which has one single genomic locus. Determination of the exon/intron splice junctions found the full-length SIRT7 protein to consist of 10 exons ranging in size from 71 bp (exon 4) to 237 bp (exon 7). The human Sirt7 open reading frame encodes a 400-aa protein with a predictive molecular weight of 44.9 kDa and an isoelectric point of 9.80. Characterization of the 5' flanking genomic region, which precedes the Sirt7 open reading frame, revealed a TATA- and CCAAT-box less promoter that lacks CpG islands. A number of AML-1 and GATA-x transcription factor binding sites were found, which remain to be further evaluated experimentally. Fluorescence in situ hybridization analysis localized the human Sirt7 gene to chromosome 17q25.3; a region which is frequently affected by chromosomal alterations in acute leukemias and lymphomas. Human SIRT7 appears to be most predominantly expressed in the blood and in CD33+ myeloid bone marrow precursor cells, while the lowest levels are found in the ovaries and skeletal muscle. Functional characteristics of SIRT7 are essentially unknown at present and remain to be further elucidated.

5' Flanking Region↗
PubMed2005

Pharmacogenomics: questions and concerns.

The progressively aging population in the western world, rising socioeconomic expenditure and increasing costs for the treatment of adverse drug reactions, lead to increasing pressure on public spending. The public acceptance of pharmacogenomics is high, therefore, because it promises individualized safe and effective treatment at lower cost. Pharmacogenomics studies the genetic polymorphisms that underlie the variability in drug response between individuals. Despite the great benefits being awaited from this new field, a number of ethical, social and legal concerns arise, which demand rapid strict international regulations in order to prevent discrimination or harm of any kind from society, industry, groups or individuals.

Delivery of Health Care↗
PubMed2005

The histone deacetylase inhibitor suberoylanilide hydroxamic acid down-regulates expression levels of Bcr-abl, c-Myc and HDAC3 in chronic myeloid leukemia cell lines.

In chronic myelocytic leukemia (CML) the activity of the Bcr-Abl tyrosine kinase is known to activate a number of molecular mechanisms, which inhibit apoptosis. In the present study, we show that the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) markedly decreases protein expression levels of Bcr-Abl and c-Myc in BV-173 cells, while in K562 cells only a minor decrease of Bcr-Abl protein levels is observed while a considerable reduction of c-Myc protein expression may only be achieved at higher concentrations of SAHA. In addition, we found BV-173 cells to be more sensitive to SAHA-induced apoptosis when compared to K562 cells. Even though earlier reports on SAHA considerably focused on its inhibitory effect on HDAC enzymatic activity, we report herein a significant down-regulation of HDAC3 protein expression levels following treatment with SAHA in BV-173 cells, but not in K562 cells. In conclusion, our results imply a molecular mechanism for SAHA-induced apoptosis in BV-173 cells, which involves decreased protein expression levels of Bcr-Abl, c-Myc and HDAC3.

Apoptosis↗
PubMed2005

Chromosomal organization and localization of the novel class IV human histone deacetylase 11 gene.

Histone deacetylases (HDACs) play a central role in the modification of chromatin structure and thus in the regulation of transcription and cellular differentiation. Based on structural and functional similarities, mammalian histone deacetylases may be grouped into four categories: class I HDACs, which are homologs of the yeast histone deacetylase RPD3; class II HDACs, which share a significant degree of homology with the yeast histone deacetylase HDA1; class III HDACs, which are closely related to the yeast SIR2 protein; and the most recently described class IV of HDACs, which comprises HDAC11-related enzymes. We have isolated and characterized the human HDAC11 genomic sequence, which spans a region of 24,074 bp and has a single genomic locus. Determination of the exon-intron splice junctions established that HDAC11 is encoded by 9 exons ranging in size from 43 bp (exon 4) to 867 bp (exon 9). Characterization of the 5' flanking genomic region, which precedes the HDAC11 open reading frame, revealed a TATA and CCAAT box-less promoter that contains a 1-kb CpG island. The 1,733-bp human HDAC11 mRNA encodes a 347 aa protein with a predictive molecular weight of 39.1 kDa and an isoelectric point of 6.88. Fluorescence in situ hybridization analysis localized the human HDAC11 gene to chromosome 3p25, a region characterized by frequent gains and losses of chromosomal material in a number of various types of cancer.

Amino Acid Sequence↗
PubMed2005

FISH-mapping and genomic organization of the NAD-dependent histone deacetylase gene, Sirtuin 2 (Sirt2).

Sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, which belongs to the Silent information regulator 2 (Sir2) family of sirtuin histone deacetylases (HDACs). The yeast Sir2 protein and its mammalian derivatives play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging. We have isolated and characterized the human Sirt2 genomic sequence, which spans a region of 20,960 bp and which has one single genomic locus. Determination of the exon-intron splice junctions found the full-length SIRT2 protein to consist of 16 exons ranging in size from 16 bp (exon 1) to 749 bp (exon 9). The 1,963-bp human Sirt2 mRNA has an open reading frame of 1,167 bp that encodes two isoforms of the SIRT2 protein: isoform 1 encodes a 389-aa protein with a predictive molecular weight of 43.2 kDa and an isoelectric point of 5.22, while isoform 2, which is lacking the first three exons, encodes a 352-aa protein with a predictive molecular weight of 39.5 kDa and an isoelectric point of 6.05. Characterization of the 5' flanking genomic region, which precedes the Sirt2 open reading frame, revealed a TATA- and CCAAT-box less promoter that contains a 0.67-kb CpG island and a number of NFkappaB and GATA transcription factor binding sites. Fluorescence in situ hybridization analysis localized the human Sirt2 gene to chromosome 19q13.1. Human SIRT2 is known to be most predominantly expressed in the brain. Since it is however severely reduced in a large number of human brain tumor cell lines, the absence of SIRT2, a potential tumor suppressor, could play a key role in the regulation of the cell-cycle within a multistep pathway that leads to full cellular transformation and, finally, the development of cellular malignancy.

Amino Acid Sequence↗
PubMed2003

Cloning and structural characterization of the human histone deacetylase 6 gene.

Histone deacetylases (HDACs) play a central role in the modification of chromatin structure and thus in the regulation of transcription and cellular differentiation. Based on structural and functional similarities, mammalian histone deacetylases may be grouped into three categories, class I HDACs, which are homologs of the yeast histone deacetylase RPD3, class II HDACs, which share a significant degree of homology with the yeast histone deacetylase HDA1 and class III HDACs which are closely related to the yeast SIR2 protein. We have isolated and characterized the human HDAC6 genomic sequence, which spans a region of 21,923 bp and which has one single genomic locus. Determination of the exon-intron splice junctions established that HDAC6 is encoded by 28 exons ranging in size from 41 bp (exon 5) to 677 bp (exon 24). Characterization of the 5' flanking genomic region, which precedes the HDAC6 open reading frame, revealed a TATA- and CCAAT-boxless promoter that contains a 1 kb CpG island. The 3,648 bp human HDAC6 mRNA encodes a 1,215 aa protein with a predictive molecular weight of 131.4 kDa. Fluorescence in situ hybridization analysis localized the human HDAC6 gene to the subband border of chromosome Xp11.22-23, a region which is characterized by frequent gains and losses of chromosomal material in several types of cancer and neurological disorders.

Amino Acid Sequence↗
PubMedDate not supplied

Phase 2 trial of the continuous IV administration of interferon-beta in patients with disseminated malignant melanoma.

BACKGROUND: Interferons have been reported to significantly contribute to tumor suppression via both induction of p53 gene expression and inhibition of angiogenesis. OBJECTIVE: The assessment of treatment toxicity and antitumoral effectiveness of continuous IV administration of interferon-beta based on an overall evaluation of laboratory, radiographic, and clinical parameters observed during the trial. METHODS: The authors treated patients with advanced malignant melanoma with continuous IV infusions of 1 x 10(6) IU interferon-beta daily ( approximately 0.6 x 10(6) IU interferon-beta/m2 daily). RESULTS: Continuous IV administration of interferon-beta had no significant effect on overall patient outcome. Interferon side effects were not a reason for treatment discontinuation in any of the patients observed during this trial. CONCLUSIONS: Continuous IV interferon-beta had no significant effect on overall patient outcome in a group of patients with advanced malignant melanoma. To our knowledge, this is the first report on the continuous IV administration of interferon-beta in patients with advanced malignant melanoma.

Aged↗