As of May 2016, the STAT5 Signaling Research Group stopped its research activities.
|Research overview||BACK TO TOP|
Signal transducer and activator of transcription STAT5 plays essential roles in regulating cell differentiation, proliferation and survival, as well as the immune response. STAT5 is normally activated by a number of cytokines (e.g., IL-2, IL-3), growth factors and hormones. Upon activation, STAT5 is phosphorylated by JAK kinases and is translocated into the nucleus where it activates the transcription of specific target genes (Cis, Osm, Bcl-x, c-Myc, …). While STAT5 activation is tightly controlled under physiological conditions, it is frequently aberrantly activated in a variety of cancers.
The STAT5 Signaling Research Group investigated the mechanism of transcriptional regulation by STAT5 in normal and cancer cells. A major focus was the identification and characterization of small-molecule inhibitors targeting STAT5 activity, thus potentially acting as cancer chemopreventive and/or chemotherapeutic agents.
Notably, we were the first to show that a class of anti-cancer agents, called deacetylase inhibitors, inhibit STAT5-mediated transcription (Rascle et al., 2003; Rascle and Lees, 2003). We recently demonstrated that deacetylase inhibitors block STAT5 activity by interfering with the function of the chromatin-associated factor Brd2, a member of the bromodomain and extra-terminal (BET) family essential for the proper recruitment of the transcriptional machinery (Pinz et al, 2015) (Figure A).
On the other hand, we identified synthetic chalcones (Pinz et al., 2014; Jobst et al., 2016; coll. with PD Dr. Sabine Amslinger, Organic Chemistry, Regensburg, Germany) and dietary isothiocyanates (sulforaphane, moringin; coll. with Prof. em. Renato Iori, CREA-CIN, Bologna, Italy; Pinz et al., 2014; Michl et al., 2016) as novel STAT5 inhibitors, targeting STAT5 signaling at various levels (Figures B, C).
|Team||BACK TO TOP|
AG Rascle in June 2013
Former lab members
|Funding||BACK TO TOP|
|Selected publications||BACK TO TOP|
Pinz, S., Unser, U., and Rascle, A.* (2016). Signal Transducer and Activator of Transcription STAT5 is recruited to c-Myc super-enhancer. BMC Mol. Biol. (in press).
Pinz, S., Unser, U., Buob, D., Fischer, P., Jobst, B., and Rascle, A.* (2015). Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function. Nucleic Acids Res. 43, 3524-45.
Pinz, S., Unser, U., and Rascle, A.* (2014). The natural chemopreventive agent sulforaphane inhibits STAT5 activity. PLoS ONE 9(6): e99391.
Pinz, S., Unser, U., Brueggemann, S., Besl, E., Al-Rifai, N., Petkes, H., Amslinger, S.*, and Rascle, A.* (2014). The synthetic α-bromo-2’,3,4,4’-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway. PLoS ONE 9(3): e90275.
Rascle, A.*, Neumann, T., Raschta, A-S., Neumann, A., Heining, E., Kastner, J., and Witzgall, R.* (2009). The LIM-Homeodomain transcription factor LMX1B regulates expression of NF-kappa B target genes. Exp. Cell Res. 315, 76-96.
Basham, B., Sathe, M., Grein, J., McClanahan, T., d’Andrea, A., Lees, E., and Rascle, A.* (2008). In vivo Identification of Novel STAT5 Target Genes. Nucleic Acids Res. 36, 3802-18.
Burrows, J.F., McGrattan, M., Rascle, A., Humbert, M., Baek K-H., and Johnston, J.A. (2004). DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks proliferation. J. Biol. Chem. 279, 13993-14000.
Rascle, A.*, Johnston, J.A., and Amati, B. (2003). Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5. Mol. Cell. Biol. 23, 4162-4173.
Rascle, A.*, and Lees, E. (2003). Chromatin acetylation and remodeling at the Cis promoter during STAT5-induced transcription. Nucleic Acids Res. 31, 6882-6890.
Rascle, A.*, Stowers R.S., Garza D., Lepesant J.A., and Hogness D.S. (2003). L63, the Drosophila PFTAIRE, interacts with two novel proteins unrelated to cyclins. Mech. Dev. 120, 617-628.
Migone, T-S.♣, Humbert, M.♣, Rascle, A.♣, Sanden, D., D'Andrea, A., and Johnston, J.A. (2001). The deubiquitinating enzyme Dub-2 prolongs cytokine-induced STAT activation and suppresses apoptosis following cytokine withdrawal. Blood 98, 1935-1941. ♣ equal contribution
Rascle, A., Ferrand, N., Gandrillon, O., and Samarut, J. (1996). Myb-Ets fusion oncoprotein inhibits T3R/c-ErbA and RAR functions: a novel mechanism of action for leukemogenic transformation by E26 avian retrovirus. Mol. Cell. Biol. 16, 6338-6351.
Rascle, A., Ghysdael, J., and Samarut, J. (1994). c-ErbA, but not v-ErbA, interferes with a putative erythroid repressor for binding to the carbonic anhydrase II promoter. Oncogene 9, 2853-2867.
(*) corresponding author
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