Protein Phosphorylation as a Key Mechanism for the Regulation of BCL-3 Activity

Constitutive NF-?B activation, a hallmark of many human cancers, upregulates anti-apoptotic gene expression and therefore disrupts the balance between apoptosis and proliferation. In some lymphomas, this constitutive NF-?B activity is the result of point mutations or translocations of the genes coding for NF-?B inhibitors, namely I?B? or p100. The BCL-3 protein is another member of the I?B family and is overexpressed in a subset of human B-cell chronic lymphocytic leukemias because of a chromosomal translocation. This oncoprotein is phosphorylated by multiple kinases including GSK3 and this phosphorylation regulates BCL-3 function by modulating its oncogenic potential and by regulating the expression of a subset of its target genes. Therefore, deciphering the NF-?B/I?B protein phosphorylations is critical in order to better understand the molecular mechanisms of NF-?B-mediated oncogenesis.