*10/22/1959. Married; two sons and a daughter
Molecular Cell Biology, Cancer Research
Associate (Apl.) Professor of Molecular Biology;
Principal Investigator; Managing Director
Regulation of gene expression in normal cells, aging cells and cancer cells; Mechanisms of tumor suppression; Functions of proteins encoded by endogenous retroviruses.
Our current work focuses primarily on novel interactions between the p53 tumor suppressor and vitamin D pathways. Vitamin D receptor (VDR) and p53 are both transcription factors that exert important tumor suppressor functions. We have shown previously a crosstalk between these signaling pathways that involves binding of VDR to p53 and Murine Double Minute homologue 2 (MDM2). Our most recent findings suggest relevance of this interaction. Wildtype-p53 comes in two flavors, carrying either a proline (P) or arginine (R) at position 72, determined by single-nucleotide polymorphism rs1042522. With respect to tumor suppression, p53-72R is a bit stronger as it is a more efficient inducer of apoptosis in response to cellular stress. P53-72P, on the other hand, is associated with increased longevity in humans for unknown reasons not related to tumor suppression, and with reduced female fertility. Moreover, there is an intriguing shift in the ratio of the allele frequencies in dependence of latitude, with p53-72R being much more frequent in the North. One potential reason for this may have been recently identified by Maureen E. Murphy and colleagues: p53-72R can control fat metabolism to support obesity. We suggest another potential evolutionary reason for the increased p53-72R frequency in the North, related to the insufficiency of vitamin D production at Northern latitudes. Through initial in silico studies on public databases of p53-induced genes and qRT-PCR follow-ups, we identified and confirmed the gene CYP24A1 as significantly stronger activated in the presence of p53-72R (the Northern p53 variant) compared to p53-72P. CYP24A1 is not a directly p53-regulated gene but is regulated by the VDR in dependence of 1,25(OH)2D3 (active vitamin D). The presence of p53-72R permitted lower 1,25(OH)2D3 levels to achieve similar VDR activity (1,25(OH)2D3-dependent CYP24A1 transcript levels) as in the presence of p53-72P. The mechanisms that underlie the increased VDR activity in the presence of p53-72R are currently being worked out.
Another area of interest is the function of proteins encoded by human endogenous retroviruses (HERVs). Np9 (Nuclear protein of 9 kDa) identified by us (and shown by others to be expressed in induced pluripotent and embryonal stem cells), was recently demonstrated by us to be exclusively produced in gorilla, chimpanzee and human and to interact with MDM2 of the p53 tumor suppressor pathway. The precise functions of Np9 are unknown.
MS, Molecular Biology, University of Bonn; PhD, Molecular Biology, University of Duesseldorf, Germany
Fellow of the Fritz-ter-Mer Foundation, 1982;
Fellow of the “Studienstiftung des deutschen Volkes“, 1985-88;
Fellow of the German Academic Exchange Service, 1988-91;
Fellow of the German Research Foundation, 1991-92;
German Society for Muscle Diseases Award (shared with J. Prudlo), 2000
Professional Experiences & Services
Associate (Apl.) Professor of Molecular Biology, University of Saarland, Carreras Center, 2006-present;
Senior Lecturer, University of Saarland, Institute of Virology, 2001-06;
Assistant Professor, University of Saarland, Institute of Virology, 1996-2001;
Research Assistant Professor, Center for Molecular Genetics, University of California, San Diego, USA, 1992-95;
Postdoctoral fellow, University of California San Diego, USA, 1988-92
Academic Editor of PLOS ONE, 2011- present;
Referee for funding bodies including German Research Foundation (DFG), Cancer Aid (Krebshilfe), Israel Science Foundation;
Referee for scientific journals including Cancer Research, Carcinogenesis, Cell Cycle, Journal of Virology, Nucleic Acids Research, Oncogene Supervision of > 50 PhD, MD, MS and BS theses, 1994-present
American Society for Biochemistry and Molecular Biology; German Society for Biochemistry andMolecular Biology; European Association for Cancer Research
>70 peer-reviewed publications in journals including Science, Genes & Development, Proceedings of the National Academy of Sciences USA, Cancer Research, Oncogene Nucleic Acids Research, Journal of Virology,
PLoS Pathogens, Cell Cycle. H-index: 33
Selected Research Papers
Identification of C/EBPα as a novel target of the HPV8 E6 protein regulating miR-203 in human keratinocytes.
PLoS Pathog 13(6): e1006406, 2017.
MicroRNA-496: A new, potentially aging-relevant regulator of mTOR.
Cell Cycle 15(8): 1108-16, 2016.
Np9, a cellular protein of retroviral ancestry restricted to human, chimpanzee and gorilla, binds and regulates ubiquitin ligase MDM2.
Cell Cycle 14(16): 2619-33, 2015.
Transcriptional repressor NIR interacts with the p53-inhibiting ubiquitin ligase MDM2.
Nucleic Acids Res. 42(6): 3565-79, 2014.
A novel mechanism of crosstalk between the p53 and NFkB pathways: MDM2 binds and inhibits p65RelA.
Cell Cycle 12(15): 2479-92, 2013.
Differential basal levels of MDM-2 transcription induced by p53-P72 and p53-R72.
Cell Cycle 9(19): 4028-30, 2010.
NIR, an inhibitor of histone acetyltransfer-ases, regulates transcription factor TAp63 and is controlled by the cell cycle.
Nucleic Acids Res. 38(19):3159-71, 2010.
Resistance of mitochondrial p53 to dominant inhibition.
Mol Cancer 12;7:54, 2008.
Epstein-Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5.
Nucleic Acids Res. 36(2): 666-75, 2008.
Physical and functional interaction between human endogenous retrovirus proteins Np9 and Rec and the Promyelocytic Leukemia Zinc Finger protein.
J Virol 81: 5607-5616, 2007.
NIR is a novel INHAT-repressor that modulates the transcriptional activity of p53.
Genes & Dev 19: 2912-2924, 2005.
Human endogenous retrovirus rec interferes with germ cell development in mice and may cause carcinoma in situ, the predecessor lesion of germ cell tumors.
Oncogene 24: 3223-3228, 2005.
Mitochondrial p53 levels parallel total p53 levels independently of stress response in human colorectal carcinoma and glioblastoma cells.
Oncogene 23: 626-636, 2004.
p21Waf1/Cip1 can protect human colon carcinoma cells against p53-dependent and p53-independent apoptosis induced by natural chemopreventive and therapeutic agents.
Oncogene 20: 3387-3398, 2001.
Motor neuron cell death in a mouse model of FALS is not mediated by the p53 cell survival regulator.
Brain Res 879: 183-187, 2000.
Quantitation of transcription and clonal selection of single living cells with beta-lactamase as reporter.
Science 279: 84-88, 1998.
Specificity of antibodies directed against Env protein of human endogenous retroviruses in patients with germ cell tumors.
Cancer Res 56: 4362-4365, 1996.
Single cell monitoring of growth arrest and morphological changes induced by transfer of wild-type p53 alleles in glioblastoma cells.
Proc Natl Acad Sci USA 92: 1008-1012, 1995.s