Bcl-3, a multifaceted modulator of NF-κB-mediated gene transcription

Abstract

The transcription factor, NF-kappaB (nuclear factor-kappaB) and associated regulatory factors make up a multi-component signaling pathway that regulates a wide range of biological processes, including cell survival, proliferation, differentiation, stress response, and death, as well as immunity and inflammation. Aberrant NF-kappaB pathway activity is known to be associated with a host of diseases, including immune deficiencies, inflammatory disorders, and cancer. Recent advances in our understanding of the inner workings of the NF-kappaB pathway have led to the development of new therapeutic strategies for the treatment of these diseases. In this review, we focus on the regulation of the NF-kappaB pathway by Bcl-3 (B cell leukemia-3), a nuclear member of the IkappaB (inhibitor of NF-kappaB) family. Both the regulation and the function of Bcl-3 will be discussed.

Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

“…Therapeutic targeting of NF-kB in disease is therefore likely to have severe consequences on normal tissues. An alternative strategy of NF-kB targeted therapy has therefore been proposed, which involves a more selective inhibition of NF-kB signaling through the putative targeting of cofactors or upstream regulators of NF-kB (45)(46)(47). Thus, the selective regulation of malignancy-associated gene targets by Bcl3 and the fact that mice with constitutive Bcl3 deficiency are viable with only minor immunologic defects (20,48), and no detrimental effects on normal mammary gland morphology or à , paired t test P < 0.05 versus control; Ãà , paired t test P < 0.05 versus Bcl3.…”

Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis

“…Also, the fact that a major effector function of IL-17 + T lymphocytes is the stimulation of G-CSF-mediated granulocyte production raises the possibility that Bcl3 control of granulopoiesis could play a critical role in regulating tolerance to self-antigens (37,38). For example, in models of Type 1 diabetes the absence of Bcl3 expression in hematopoietic cells has been recently shown to exacerbate IL-17-associated destruction of islets (39).…”

Characterization of the Core Elements of the NF-κB Signaling Pathway of the Sea Anemone Nematostella vectensis

“…Nv-Bcl-3 also interacted directly with Nv-NF-B and blocked its ability to activate transcription of a reporter locus in A293 cells. Human Bcl-3 can also interact directly with p50 and p52 homodimers and, under different circumstances, can be an activator or repressor of NF-B-dependent transcription (25). Given that our experiments were performed in human A293 cells, it is unclear whether Nv-Bcl-3 acts as a repressor, activator, or both for Nv-NF-B in Nematostella.…”