Research Report 2000 - MDC

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Selected Publications Gaudet, F., Talbot, D., Leonhardt, H., and Jaenisch, R. (1998) A short DNA methyltransferase isoform restores methylation in vivo. J. Biol. Chem. 273, 32725-32729. Krämer, J., Aguirre-Arteta, A. M., Thiel, C., Gross, C. M., Dietz, R., Cardoso, M.C., and Leonhardt, H. (1999) A novel isoform of the smooth muscle cell differentiation marker smoothelin. J. Mol. Med. 77, 294-298. von Harsdorf, R., Hauck, L., Mehrhof, F., Wegenka, U., Cardoso, M. C., and Dietz, R. (1999) E2F1 overexpression in cardiomyocytes induces downregulation of p21CIP1 and p27KIP1 and release of active cyclindependent kinases in the presence of Insulin-like growth factor I. Circ. Res. 85, 128-136. Engel, F. B., Hauck, L., Cardoso, M. C., Leonhardt, H., Dietz, R., and von Harsdorf, R. (1999) A mammalian myocardial cell-free system to study cell cycle re-entry in terminally differentiated cardiomyocytes. Circ. Res. 85, 294-301. Derer, W., Easwaran, H. P., Knopf, C. W., Leonhardt, H., and Cardoso, M. C. (1999) Direct protein transfer to terminally differentiated muscle cells. J. Mol. Med. 77, 609-613. Cardoso, M.C., and Leonhardt, H. (1999) DNA methyltransferase is actively retained in the cytoplasm during early development. J. Cell Biol. 147, 25-32. 88 Cell Biology of Cardiovascular Diseases Structure of the Group Group leader Dr. Heinrich Leonhardt Scientists Dr. Jochen Krämer* Dr. Christina Quensel Dr. Jean B. Margot Dr. Jörg Meding Graduate students François Gaudet Technical assistant Ingrid Grunewald * part of the period reported. Differentiation and Cell Cycle Regulation in Muscle Cells Structure of the Group Group leader Dr. M. Cristina Cardoso Scientists Dr. Hans-Peter Rahn Dr. Anje Sporbert Dr. Wolfgang Derer Graduate students Ana M. Aguirre-Arteta Hariharan P. Easwaran
Surgical Oncology Peter M. Schlag Tumor progression, invasion and metastasis W. Kemmner, U. Stein, W. Walther, W. Haensch, H. Schwabe in cooperation with U. Karsten, J. Behrens, W. Birchmeier Tumor-associated alterations of cell surface glycosylation play an important role in invasion and metastasis of carcinoma cells. Accordingly, expression of the glycosyltransferases responsible for glycosylation is altered in tumor cells and this influences their cell adhesion properties. Therefore, sense- and antisense- transfectants of such glycosyltransferases have been established. Specific antisense oligodeoxynucleotides, which inhibit enzyme activity have been studied in connection with a possible clinical treatment of metastasis. Another of our interests are Thomsen- Friedenreich (TF) related tumorassociated carbohydrates. We have found that the balance between Oglycan chain termination through sialylation and chain extension through N-acetylglucosaminylation is disturbed in colorectal carcinomas. Patients with high expression of sialyltransferase ST6GalNAc-II are at a significantly higher risk of death and have a shorter overall survival. We have identified new genes involved in the organ-specific metastases of colon carcinoma by differential display using surgical specimens. Three ESTs have been identified that are differentially expressed in metastasizing versus non-metastasizing primary tumors, distinct metastases (preferentially liver and lung) or normal epithelium. Expression of candidate genes was confirmed by quantitative real time RT-PCR. Expression of the transcription factor GLI has been analyzed in sarcomas and during metastasis and we found significantly enhanced GLI expression in tumors compared with normal tissues. Moreover, GLI expression correlated with the grading of the sarcomas. Thus, enhanced GLI expression might be indicative of aggressiveness and dedifferentiation of mesenchymal tumors. Multidrug resistance and hyperthermia U. Stein, W. Walther, K. Jürchott in cooperation with B. Rau, P. Hohenberger, P.-U. Tunn Multidrug resistance (MDR) still limits the successful chemotherapy of cancer. The expression of MDRassociated genes is inducible by external stress factors such as heat shock. This is controlled by stress responsive elements within the gene promoters and might be a molecular mechanism that hinders chemotherapy. Thus, the impact of hyperthermia on the induction of MDR-associated genes has been investigated in colorectal carcinomas, before and after radiochemotherapy or radiochemothermotherapy, respectively. In the majority of the cases analyzed, the risk of inducing MDR gene expression by hyperthermia has been found to be minimal in a clinical setting. Investigations analyzing the influence of hyperthermia on the expression of the MDR genes, 2 – 48h following heat treatment, are currently underway. The impact of isolated hyperthermic limb perfusion on the expression/induction of MDRassociated genes had been examined in soft tissue sarcomas and melanomas at several time points prior to, during and post treatment. So far, induction of certain MDRassociated genes, such as MDR1, MRP1, and LRP, has been observed within hours of hyperthermic treatment. Heat shock-induced expression of MDR genes should be taken into account when combining hyperthermia with MDR-associated cytostatic drugs. Detection and pathobiology of solid tumors with microsatellite instability K. Kölble, B. Barthel, L. Estevéz- Schwarz, K. Krause, H. Pidde, O. M. Ullrich in cooperation with M. Dietel and S. Scherneck Somatic alterations in simple repetitive sequences that are present as microsatellites throughout the human genome are characteristic of a subset of human tumors with defects in DNA mismatch repair. Germline mutations in various DNA mismatch repair genes dramatically increase an individual’s susceptibility to various neoplasms and are the molecular basis for the syndrome of hereditary nonpolyposis colorectal carcinoma (HNPCC). HNPCC is characterized by the early and familial occurrence of intestinal and extraintestinal cancers. Collaborative efforts to better define the epidemiological, clinical and pathomorphologic features of this cancer susceptibility syndrome are critical for elucidating its pathogenetic pathways and improving the clinical management of patients and gene carriers. Potential cases of HNPCC, reported locally as well as regionally, have been registered and investigated by a combination of detailed clinical and pedigree studies, histopathology, immunohistology, microsatellite instability (MSI) analysis and germline sequencing. However, identification of HNPCC carriers by biochemical screening prior to complete genomic sequencing could significantly improve these existing cancer preventive strategies. Cell-free DNA in the blood of cancer patients has been shown to harbor microsatellite alterations frequently matching those of the primary tumors. We have investigated the patterns of such microsatellite alterations in sera and microdissected tumors of colorectal cancer patients. Using an integrative morphological, immunohistological and genetic approach, high-grade serum MSI was preferentially found in individuals with mismatch repair-defective tumors. Although the molecular mechanisms of tumoral DNAshedding remain to be elucidated, its detection by serum DNA microsatellite analysis appears to be useful for the diagnosis and monitoring of neoplasms caused by defective DNA mismatch repair. The subsequent development of a 89
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Research Report 2000 Covers the Per
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Molecular Therapy Molecular and Dev
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The quantum theory, that provided a
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Introduction Clinical Research The
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Genome Research in Berlin- Brandenb
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External Evaluation Over the period
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Congresses In the years reported, t
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Awards A number of prestigious priz
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Genetics, Bioinformatics and Struct
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disorders. Various MDC groups have
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Steen R.G., Kwitek-Black A.E., Glen
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Selected Publications Binas, B., Da
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Technology transfer Based on the fu
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Selected Publications Müller, D.N.
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Selected Publications Hennies, H.C.
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Somatic genetic alterations in brea
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Clinical and Molecular Genetics of
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Selected Publications Toka, H.R., B
Page 37 and 38: Lbx1, c-met and the control of cell
Page 39 and 40: Selected Publications Moore, A., Mc
Page 41 and 42: Selected Publications Herz, J., Wil
Page 43 and 44: We aim to study the genetic epidemi
Page 45 and 46: Nucleation Nucleation as a pre-requ
Page 47 and 48: Selected Publications Damaschun, G.
Page 49 and 50: Selected Publications Yuan, T., Wal
Page 51 and 52: stability. By determining the struc
Page 53 and 54: Role of Protein Dynamics in Enzyme
Page 55 and 56: Modeling Nucleic Acid Structure and
Page 57 and 58: Conformation, Stability and Interac
Page 59 and 60: Protein Structure Analysis and Prot
Page 61 and 62: Cell Growth and Differentiation 61
Page 63 and 64: dendritic cells (DC). Adoptive tran
Page 65 and 66: developmental pathway that may invo
Page 67 and 68: Regulation of Transcription in Mamm
Page 69 and 70: Differentiation and Growth Control
Page 71 and 72: Cell cycle-dependent transcriptiona
Page 73 and 74: Cell Cycle Regulation Hans-Dieter R
Page 75 and 76: Epithelial Differentiation, Invasio
Page 77 and 78: Selected Publications Hartmann, G.,
Page 79 and 80: Selected Publications Behrens, J.,
Page 81 and 82: Selected Publications Karsten, U.,
Page 83 and 84: Depressed contractility in human he
Page 85 and 86: Understanding calcium handling prot
Page 87: VSMCs. We have cloned and character
Page 91 and 92: Ubiquitin System and Endoplasmic Re
Page 93 and 94: P450 Cytochromes and the Endoplasmi
Page 95 and 96: Vascular Biology Hermann Haller Thi
Page 97 and 98: Selected Publications Gollasch, M.,
Page 99 and 100: Electron Microscopy Members of the
Page 101 and 102: Molecular Therapy 101
Page 103 and 104: Hematology, Oncology and Tumor Immu
Page 105 and 106: Selected Publications Sturm, I., K
Page 107 and 108: Selected Publications Westermann, J
Page 109 and 110: fractions. The hematopoietic potent
Page 111 and 112: Interaction of pharmacologically ac
Page 113 and 114: Molecular Basis of Congestive Heart
Page 115 and 116: Selected Publications Schneider, G.
Page 117 and 118: different murine and human tumor ce
Page 119 and 120: Molecular and Cell Biology of Hemat
Page 121 and 122: Phospholipids Dietrich Arndt Cytoto
Page 123 and 124: Regulation and Deregulation of Cell
Page 125 and 126: Evolution, Regulation and Genetic A
Page 127 and 128: Molecular and Developmental Neurosc
Page 129 and 130: Cellular Neurosciences Helmut Kette
Page 131 and 132: Growth Factor and Regeneration Gary
Page 133 and 134: Synapse Formation and Function Fran
Page 135 and 136: Developmental Neurobiology Fritz G.
Page 137 and 138: Selected Publications Volkmer, H.,
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Structure and Organization 139
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Prof. Dr. Hans Meyer President of t
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Supporting Divisions Safety The div
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Press and Public Relations Research
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Purchasing and Materials Management
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Computing The computing group of th
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Awards Thomas Biederer Boehringer-M
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Index A Abdul, Yetunde 90 Aguirre-A
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H Haase, Hannelore 85, 97, 100, 142
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Q Qin, Zhihai 107, 117 Quass, Petra
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Board of Trustees Chair Wolf-Michae
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