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Gamma interferon down-regulates Fer and induces its association with inactive Stat3 in colon carcinoma cells
Kira Orlovsky1, Livia Theodor, Hana Malovani
1Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Abstract:
Gamma interferon (IFN-gamma) is a regulator of cell growth, which suppresses the proliferation of HT-29 colon carcinoma cells. Here we show that in HT-29 cells IFN-gamma transiently increased the cellular level of the tyrosine kinase Fer, whose functioning was found to be essential for the proliferation of malignant cell-lines. The transient elevation in the level of Fer, was followed by its down-regulation, an effect which was most prominent after 6-8 h of IFN-gamma treatment. Up- and down-regulation of Fer was paralleled by the activation and subsequent deactivation of Stat3, which is a potent oncogene and a putative substrate of the tyrosine kinase Fer. Moreover, IFN-gamma induced the association of Fer and Stat3 and the newly formed complex was most stable at the down-regulated states of the two proteins. Formation of the Fer/Stat3 complex was accompanied by an attenuation in cell-cycle progression and accumulation of cells in the G1 phase. Thus, Fer and Stat3 are two proliferation-promoting factors whose down-regulation could contribute to the cytostatic activity of IFN-gamma in colon carcinoma cells.
Insights
Gamma interferon (IFN-gamma) suppresses colon cancer cell growth by transiently increasing and then decreasing the tyrosine kinase Fer and the oncogene Stat3. Their complex formation leads to cell cycle arrest, contributing to IFN-gamma
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Gamma interferon (IFN-gamma) is known to regulate cell growth and suppress colon carcinoma cell proliferation.
- The tyrosine kinase Fer and the oncogene Stat3 are implicated in malignant cell-line proliferation.
Purpose of the Study:
- To investigate the role of Fer and Stat3 in IFN-gamma-mediated suppression of HT-29 colon carcinoma cell proliferation.
- To elucidate the molecular mechanisms underlying IFN-gamma's cytostatic effects.
Main Methods:
- Treatment of HT-29 colon carcinoma cells with IFN-gamma.
- Analysis of cellular levels and activation states of Fer and Stat3.
- Assessment of Fer-Stat3 complex formation.
- Cell cycle progression analysis.
Main Results:
- IFN-gamma transiently increased Fer levels, followed by down-regulation, peaking at 6-8 hours.
- Fer up- and down-regulation paralleled Stat3 activation and deactivation.
- IFN-gamma induced Fer-Stat3 complex formation, most stable during down-regulation.
- Fer/Stat3 complex formation correlated with G1 phase cell cycle arrest.
Conclusions:
- Fer and Stat3 are proliferation-promoting factors in colon carcinoma cells.
- Down-regulation of Fer and Stat3 contributes to the cytostatic activity of IFN-gamma.
- The Fer-Stat3 complex plays a critical role in mediating IFN-gamma's anti-proliferative effects.