STAT1 and STAT3 - mechanisms of interaction and inhibition of signaling

The aim of this project is to reveal the mechanisms of the STAT-mediated gene transcription and of the interplay between two STAT proteins, STAT3 and STAT1.

Mitogenic signaling is important for cancer cells to acquire self-sufficiency for their growth. The growth factors and cytokines and GF receptors illegitimately activated on the surface of cancer cells stimulate signaling cascades that converge at the transcription factor with oncogenic properties, STAT3. It is now well established that STAT3 is activated in a large variety of tumors and blocking STAT3 results in tumor cell death1. STAT3 binds to a conserved element in the enhancers of genes, mostly involved in cell proliferation or survival. Another transcription factor from the STAT family, STAT1, binds to the same DNA consensus element as STAT3. In contrast to STAT3, however, it activates a different set of genes and usually promotes cell cycle arrest and apoptosis.

The group in Cleveland Clinic has previously found that in the absence of STAT1, IFN-gamma is able to activate STAT3 and some of the STAT-1 responsive genes, suggesting that STAT3 is able to substitute STAT1 at some of the promoters Both STAT1 and STAT3 can also repress transcription. Interestingly, STAT1 represses transcription of some STAT3-dependent genes, such as Bcl-2 and Bcl-XL, VEGF and c-myc. Thus, the group in Cleveland Clinic demonstrated that PDGF-induced STAT3-mediated activation of c-myc promoter is down-regulated by IFN-gamma in a STAT-1-dependent fashion

Our group has previously found that cytokine IFN-alpha that activates STAT1, counteracted STAT3 activity in the IL-6-dependent myeloma cell lines. In the ongoing studies we investigate whether activated STAT1 is able to inhibit STAT3 DNA binding in vitro and STAT3-mediated expression of reporter genes in transfection experiments. Our goal is to reveal the molecular mechanisms that underlie the repression of STAT3-mediated transcription by activated STAT1.

Collaborative contribution

This project is performed in collaboration with Prof. G.R. Stark, Department of Molecular Genetics, Lerner Research institute, Cleveland Clinic, Cleveland, Ohio, USA


The STATs of cancer--new molecular targets come of age.
Yu H, Jove R
Nat. Rev. Cancer 2004 Feb;4(2):97-105

Alternative activation of STAT1 and STAT3 in response to interferon-gamma.
Qing Y, Stark G
J. Biol. Chem. 2004 Oct;279(40):41679-85

Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways.
Ramana C, Grammatikakis N, Chernov M, Nguyen H, Goh K, Williams B, et al
EMBO J. 2000 Jan;19(2):263-72

Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity.
Thyrell L, Arulampalam V, Hjortsberg L, Farnebo M, Grandér D, Pokrovskaja Tamm K
Exp. Cell Res. 2007 Nov;313(19):4015-24