Ralf Janknecht
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EDUCATION
Diplom, Biology and Chemistry, University of Bochum, Germany
Ph.D., Biochemistry, University of Bochum, Germany
RESEARCH SUMMARY
Precise control of gene expression is a prerequisite for cellular homeostasis and safeguards against tumor development. Our long-term objective is to understand how dysregulation of DNA-binding transcription factors and coactivators contributes to carcinogenesis, which may help to develop novel strategies of cancer treatment and detection.
In particular, we focus on a downstream target of several prominent human oncoproteins, the transcription factor ETV1/ER81, and JMJD proteins that regulate chromatin function. Using a great variety of in vitro and in vivo technologies, we endeavor to elucidate how these molecules modulate normal cell function and what their roles are in the development of cancer.
The ETV1/ER81 transcription factor
ETV1 (also called ER81) belongs to the ETS class of DNA-binding transcription factors. Its activity is greatly stimulated by the Raf, Ras and HER2/Neu oncoproteins through the induction of posttranslational modifications in ETV1. Moreover, chromosomal translocations involving ETV1 are found in prostate carcinomas and Ewing sarcomas, and mouse models overexpressing ETV1 develop prostatic intraepithelial neoplasia. Altogether, these data indicate that aberrant activation of ETV1 and its target genes is an underlying cause of cancer. Indeed, we have identified several ETV1 target genes, whose dysregulation is involved in cancer formation. These include hTERT, the catalytic subunit of telomerase that is required for immortalization of the vast majority of cancer cells; Smad7, an inhibitor of TGF-b-mediated tumor surveillance; MMP-1, a metalloproteinase involved in tumor invasion and metastasis; and Rcl, a hitherto scarcely characterized putative proto-oncogene.
In the future, we would like to unravel the consequences of various posttranslational modifications on ETV1 function, study how other transcription factors interfere with ETV1 activity, and analyze the physiological functions of its target gene, Rcl.
JMJD proteins
JMJD proteins are implicated in chromatin regulation and often possess the ability to demethylate lysine or arginine residues on histones and other proteins. Also, they are involved in developmental processes, and several JMJD proteins are suspected to be oncoproteins or tumor suppressors. We have cloned the majority of the 30 known human JMJD proteins and started searches for interaction partners. For instance, we found that JMJD2 proteins are pivotal cofactors of androgen receptor. Since JMJD2 expression is upregulated in prostate tumors, this suggests one mechanism of how JMJD2 proteins contribute to carcinogenesis by aberrantly stimulating androgen receptor, the key villain in prostate tumors.
Our future goals are to analyze how JMJD proteins modulate chromatin structure, how they impact on cell physiology, how their knock-out or overexpression in mice will affect development and tumor formation, and screen for small molecule JMJD inhibitors to fight cancer.
RECENT PUBLICATIONS
1. Shin, S. and Janknecht, R. Diversity within the JMJD2 histone demethylase family. Biochem. Biophys. Res. Commun. 353:973-977, 2007.
2. Shin, S. and Janknecht, R. Concerted activation of the Mdm2 promoter by p72 RNA helicase and the coactivators p300 and P/CAF. J. Cell. Biochem. 101:1252-1265, 2007.
3. Shin, S. and Janknecht, R. Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D. Biochem. Biophys. Res. Commun. 359:742-746, 2007.
4. Shin, S., Rossow, K. L., Grande, J. P. and Janknecht, R. Involvement of RNA helicases p68 and p72 in colon cancer. Cancer Res. 67:7572-7578, 2007.
5. Smith, E. H., Janknecht, R. and Maher, L. J. Succinate inhibition of a-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum. Mol. Genet. 16:3136-3148, 2007.
6. Kim, T.-D., Shin, S. and Janknecht, R. Repression of Smad3 activity by histone demethylase SMCX/JARID1C. Biochem. Biophys. Res. Commun. 366:563-567, 2008.
7. Lee, D., Park, C., Lee, H., Lugus, J. J., Kim, S. H., Arentson, E., Chung, Y. S., Gomez, G., Kyba, M., Lin, S., Janknecht, R., Lim, D.-S. and Choi, K. ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell 2:497-507, 2008.
8. Shin, S., Bosc, D. G., Ingle, J. N., Spelsberg, T. C. and Janknecht, R. Rcl is a novel ETV1/ER81 target gene upregulated in breast tumors. J. Cell. Biochem. 105:866-874, 2008.
9. Hamada, S., Kim, T.-D., Suzuki, T.*, Itoh, Y., Tsumoto, H., Nakagawa, H., Janknecht, R.* and Miyata, N.* Synthesis and activity of N-oxalylglycine and its derivatives as Jumonji C-domain-containing histone lysine demethylase inhibitors. Bioorg. Med. Chem. Lett. 19:2852-2855, 2009. *Co-corresponding authors.
10. Shin, S., Kim, T.-D., Jin, F., van Deursen, J. M., Dehm, S. M., Tindall, D. J., Grande, J. P., Munz, J.-M., Vasmatzis, G. and Janknecht, R. Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81. Cancer Res. 69:8102-8110, 2009.
11. Mooney, S. M., Grande, J. P., Salisbury, J. L. and Janknecht, R. Sumoylation of p68 and p72 RNA helicases affects protein stability and transactivation potential. Biochemistry 49:1-10, 2010.
MAILING ADDRESS
University of Oklahoma Health Sciences Center
Biomedical Research Center 1464
975 NE 10th Street
Oklahoma City, OK 73104, USA
Phone: (405) 271-8001 x 47420
Fax: (405) 271-3548