Ralf Janknecht

Professor, Department of Cell Biology

EDUCATION

Diplom, Biology and Chemistry, University of Bochum, Germany
Ph.D., Biochemistry, University of Bochum, Germany
Habilitation, Molecular Biology, Hannover Medical School, 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 epigenetic regulators contributes to the formation of tumors and other diseases, which may help to develop novel strategies of clinical treatment. In particular, we focus on the oncogenic transcription factor ETV1 and the JMJD epigenetic regulators. Using a variety of in vitro and in vivo technologies, we endeavor to elucidate how these proteins modulate normal cell function and contribute to the development of tumors, metabolic disorders and other diseases.

The ETV1 transcription factor

ETS variant 1 (ETV1) belongs to the ETS class of DNA-binding transcription factors. Its activity is greatly stimulated by the RAF, RAS and HER2 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 MMP7, a metalloproteinase that plays an important role in tumor invasion and metastasis, hTERT, the catalytic subunit of telomerase whose overexpression causes immortalization, and RCL, a hitherto scarcely characterized dNMP N-glycosidase and putative proto-oncogene.

In the future, we would like to unravel the consequences of various posttranslational modifications on ETV1 function, study how other proteins interfere with ETV1 activity, and analyze the physiological functions of RCL in normal and tumor cells.

The JMJD epigenetic regulators

Jumonji C domain-containing (JMJD) proteins are implicated in chromatin regulation and often possess the ability to demethylate lysine residues on histones. Also, they are involved in developmental processes, and several JMJD proteins are suspected to be oncoproteins or tumor suppressors. We have initiated studies on many of the 32 known human JMJD proteins and already identified several seminal interaction partners. For instance, we found that JMJD2 proteins bind to and regulate androgen and estrogen receptors, the key villains in prostate or breast tumors. In addition, JMJD2A binds to and synergizes with ETV1 to drive prostate tumorigenesis and JMJD2A expression is correlated with the aggressiveness of the disease. These findings highlight that JMJD2A is a valid new target for therapeutic inhibition.

Our future goals are to analyze how JMJD proteins modulate chromatin structure, how they impact on cell physiology, which posttranslational modifications regulate their function, and how their knockout or overexpression in mice will affect development, metabolism and neoplasia.

 
RECENT PUBLICATIONS

1.       Kim TD, Shin S, Berry WL, Oh S, Janknecht R (2012). The JMJD2A demethylase regulates apoptosis and proliferation in colon cancer cells. J Cell Biochem 113, 1368-1376.

2.       Oh S, Shin S, Janknecht R (2012). ETV1, 4 and 5: An oncogenic subfamily of ETS transcription factors. Biochim Biophys Acta 1826, 1-12.

3.       Oh S, Janknecht R (2012). Histone demethylase JMJD5 is essential for embryonic development. Biochem Biophys Res Commun 420, 61-65.

4.       Kim TD, Oh S, Shin S, Janknecht R (2012). Regulation of tumor suppressor p53 and HCT116 cell physiology by histone demethylase JMJD2D/KDM4D. PLoS One 7, e34618.

5.       DiTacchio L, Bowles J, Shin S, Lim DS, Koopman P, Janknecht R (2012). Transcription factors ER71/ETV2 and SOX9 participate in a positive feedback loop in fetal and adult mouse testis. J Biol Chem 287, 23657-23666.

6.       Berry WL, Shin S, Lightfoot SA, Janknecht R (2012). Oncogenic features of the JMJD2A histone demethylase in breast cancer. Int J Oncol 41, 1701-1706.

7.       Shin S, Oh S, An S, Janknecht R (2013). ETS variant 1 regulates matrix metalloproteinase-7 transcription in LNCaP prostate cancer cells. Oncol Rep 29, 306-314.

8.       Berry WL, Janknecht R (2013). KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res 73, 2936-2942.

9.       Oh S, Shin S, Lightfoot SA, Janknecht R (2013). 14-3-3 proteins modulate the ETS transcription factor ETV1 in prostate cancer. Cancer Res 73, 5110-5119.

10.     Berry WL, Kim TD, Janknecht R (2014). Stimulation of beta-catenin and colon cancer cell growth by the KDM4B histone demethylase. Int J Oncol 44, 1341-1348.

11.     Kim TD, Fuchs JR, Schwartz E, Abdelhamid D, Etter J, Berry WL, Li C, Ihnat MA, Li PK, Janknecht R (2014). Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells and identification of curcuminoids as JMJD2 inhibitors. Am J Transl Res 6, 236-247.

12.     Kim TD, Jin F, Shin S, Oh S, Lightfoot SA, Grande JP, Johnson AJ, van Deursen JM, Wren JD, Janknecht R (2016). Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1. J Clin Invest 126, 706-720.

13.     Kim TD, Shin S, Janknecht R (2016). ETS transcription factor ERG cooperates with histone demethylase KDM4A. Oncol Rep 35, 3679-3688.

14.     Kim TD, Oh S, Lightfoot SA, Shin S, Wren JD, Janknecht R (2016). Upregulation of PSMD10 caused by the JMJD2A histone demethylase. Int J Clin Exp Med 9, 10123-10134.


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

ralf-janknecht@ouhsc.edu