Group Institut Cochin: NF-kappaB, Differentiation and Cancer

Team leader : Véronique BAUD

Twenty years after their discovery, it is evident that the importance of the NF-kappaB transcription factors is continuing to grow due to their central role in many situations of cellular and organismal challenge. NF-kappaB plays a critical role in the immune and inflammatory responses, but also controls cell growth and protect cell from apoptosis. More recently, the relevance of NF-kappaB in tumor maintenance, tumor development and possibly even in tumor initiation is becoming more evident. NF-kappaB genes are constitutively activated, amplified or overexpressed in many human leukemias and lymphomas, including B and T-cell lymphomas and acute myeloblastic leukemias. It has also been shown that NF-kappaB plays an important role in inducing resistance to chemotherapy, therefore participating in tumor development. It thus emerges that getting new insights into the regulation of NF-kappaB activity and specificity is required to better understand the molecular mechanisms underlying hematopoietic cancer development and chemotherapy resistance.

In mammals, the NF-kappaB family is composed of five members, RelA (p65), RelB, cRel (Rel), NF-kappaB1 (p50 and its precursor p105) and NF-kappaB2 (p52 and its precursor p100). These proteins form various homo- and heterodimeric complexes, the activity of which is regulated by two main pathways. The first one, known as the canonical NF-kappaB activation pathway, mainly applies to RelA/p50 dimers which, under non stimulated conditions, are sequestered in the cytoplasm through interactions with inhibitory proteins of the IkappaB family. Following stimulation with a broad range of stimuli such as cytokines, virus, genotoxic agents and radiations, the IkappaB molecules are phosphorylated by the IkappaB kinase complex (IKK) at specific serine residues, leading to their ubiquitination and degradation by the proteasome pathway. RelA/p50 dimers are subsequently released and free to translocate into the nucleus to activate the transcription of various target genes.

In our research group, we more specifically study the function and regulation of RelB, a NF-kappaB member that is essential to mature dendritic cell function, B cell proliferation and limitation of the expression of proinflammatory mediators in fibroblasts. In the past few months, we have characterized a new NF-kappaB signaling pathway stimulated by several members of the TNF family (e.g. BAFF, lymphotoxin beta) that leads to the specific activation of RelB . This so-called alternative NF-kappaB activation pathway is based on the inducible processing of p100, the main RelB inhibitor, resulting in RelB/p50 and RelB/p52 nuclear translocation and DNA binding. Most importantly, all these studies point out to a crucial role for the alternative pathway (RelB) in controlling the development, organization and function in lymphoid tissue. We have also recently observed that RelB activity is abnormally regulated in several hematopoietic tumors such as B- and T- cell lymphomas and acute T cell lymphocytic leukemias (T-ALL). In some cases, RelB DNA binding activity even appears to be the predominant NF-kappaB activity, suggesting that the alternative pathway under certain circumstances might represent the major NF-kappaB activity. Therefore it now clearly appears that efficient anti-tumor strategies based on inhibition of NF-kappaB activity require not only the inhibition of the canonical pathway (RelA) but the alternative pathway (RelB) as well.

To better understand the mechanisms of regulation of RelB activity and how its activation or inhibition participates in the control of cell growth, differentiation and apoptosis during normal and malignant hematopoiesis, our research program focuses on the following specific aims :

- Identification of new interacting partners that regulate RelB activity

- Identification of RelB specific target genes in primary B cells

- RelB in the control of cell proliferation and apoptosis

- RelB in the development of lymphomas and leukemias