Gamma interferon down-regulates Fer and induces its association with inactive Stat3 in colon carcinoma cells.
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.
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Kira
K
Orlovsky
Livia
L
Theodor
Hana
H
Malovani
Yehuda
Y
Chowers
Uri
U
Nir
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C052602:proto-oncogene protein c-fes-fps; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases