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Controlling Nuclear Jaks and Stats for Specific Gene Activation by Ifn γ and Other Cytokines: A Possible Steroid-like
Howard M Johnson1, Ezra Noon-Song, Chulbul M Ahmed
1Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA.
Abstract:
The mechanism of specific gene activation by cytokines that use JAK/STAT signalling pathway is unknown. There are four different types of JAKs and seven different types of STATs. In the classical model of signaling, ligand interacts solely with the receptor extracellular domain, which triggers JAK activation at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific gene activation, including associated epigenetic changes that cause heterochromatin destabilization. Ligand, receptor, and JAKs play no further role in the classical model. Given the limited number of STATs and the activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on gamma interferon (IFNγ), we have shown that ligand, receptor, and activated JAKs are involved in nuclear events that are associated with specific gene activation. In this model, receptor subunit IFNGR1 functions as a transcription/cotranscription factor and the JAKs are involved in key epigenetic events that are required for specific gene activation. The model has implications for gene activation in cancer as well as stem cell differentiation.
Insights
The JAK/STAT pathway
Area of Science:
- Molecular Biology
- Cell Signaling
- Epigenetics
Background:
- The JAK/STAT signaling pathway regulates gene expression in response to cytokines.
- Specificity in this pathway is not well understood, despite limited numbers of Janus kinases (JAKs) and Signal transducer and activator of transcription (STATs).
- The classical model posits limited roles for ligands, receptors, and JAKs after initial signaling events.
Purpose of the Study:
- To elucidate the mechanism of specific gene activation mediated by the JAK/STAT pathway.
- To investigate the roles of ligand, receptor, and JAKs in nuclear events of gene activation, particularly for gamma interferon (IFNγ).
Main Methods:
- Focus on gamma interferon (IFNγ) signaling.
- Investigated the involvement of ligand, receptor, and activated JAKs in nuclear events.
- Characterized the function of the IFNGR1 receptor subunit and JAKs in gene activation and epigenetic modifications.
Main Results:
- Demonstrated that ligand, receptor, and activated JAKs participate in nuclear events for specific gene activation.
- Identified the receptor subunit IFNGR1 as a transcription/cotranscription factor.
- Showed JAKs are crucial for epigenetic events essential for specific gene activation.
Conclusions:
- The classical JAK/STAT signaling model is incomplete.
- Receptor subunits and JAKs play active roles in the nucleus during gene activation.
- This revised model has implications for understanding gene regulation in cancer and stem cell differentiation.
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