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NF-kappaB activity is constitutively elevated in c-Abl null fibroblasts
Rachel A Liberatore1, Stephen P Goff, Irene Nunes
1Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Abstract:
The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase involved in many cellular processes, including signaling from growth factor and antigen receptors, remodeling the cytoskeleton, and responding to DNA damage and oxidative stress. Many downstream pathways are affected by c-Abl. Elevated c-Abl kinase activity can inhibit NF-kappaB activity by stabilizing the inhibitory protein IkappaB alpha, raising the possibility that c-Abl-deficient cells might have increased NF-kappaB activity. We examined the levels of NF-kappaB activity in primary mouse embryonic fibroblasts (MEFs) derived from wild-type and c-Abl knockout mice and found that the knockout MEFs indeed exhibited elevated NF-kappaB activity in response to stimulation as well as constitutively elevated NF-kappaB activity. Thus, endogenous c-Abl is a negative regulator of basal and inducible NF-kappaB activity. Examination of various points of NF-kappaB regulation revealed that unstimulated c-Abl knockout MEFs do not exhibit an increase in IkappaB alpha degradation, p65/RelA nuclear translocation, or DNA binding of NF-kappaB subunits. They do, however, show reduced levels of the histone deacetylase HDAC1, a negative regulator of basal NF-kappaB activity. Unstimulated c-Abl knockout MEFs are less responsive to induction of NF-kappaB activity by trichostatin A, an HDAC inhibitor, suggesting that c-Abl might play a role in the HDAC-mediated repression of basal NF-kappaB activity.
Insights
Endogenous c-Abl acts as a negative regulator of NF-kappaB activity. c-Abl-deficient cells show increased NF-kappaB activity due to reduced HDAC1 levels, impacting cellular signaling pathways.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Oncogenes
Background:
- c-Abl is a nonreceptor tyrosine kinase regulating crucial cellular processes.
- c-Abl influences pathways including growth factor signaling, cytoskeleton remodeling, and stress responses.
- Elevated c-Abl kinase activity can inhibit NF-kappaB by stabilizing IkappaB alpha.
Purpose of the Study:
- To investigate the role of endogenous c-Abl in regulating NF-kappaB activity.
- To determine if c-Abl deficiency leads to altered NF-kappaB activation.
- To elucidate the mechanisms by which c-Abl affects NF-kappaB regulation.
Main Methods:
- Primary mouse embryonic fibroblasts (MEFs) from wild-type and c-Abl knockout mice were used.
- NF-kappaB activity was measured in response to stimulation.
- Levels of IkappaB alpha, p65/RelA, and HDAC1 were examined.
- Responsiveness to trichostatin A (HDAC inhibitor) was assessed.
Main Results:
- c-Abl knockout MEFs exhibited elevated basal and inducible NF-kappaB activity.
- No significant changes in IkappaB alpha degradation, p65/RelA translocation, or DNA binding were observed in unstimulated knockout MEFs.
- Knockout MEFs showed reduced levels of the negative regulator HDAC1.
- c-Abl knockout MEFs were less responsive to HDAC inhibition by trichostatin A.
Conclusions:
- Endogenous c-Abl negatively regulates both basal and inducible NF-kappaB activity.
- c-Abl may play a role in HDAC-mediated repression of basal NF-kappaB activity.
- Reduced HDAC1 levels in c-Abl-deficient cells contribute to elevated NF-kappaB activity.
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