Constitutively activated nuclear factor (NF)-
IntroductionNuclear factor (NF)-B transcription factors regulate the expression of numerous genes that are necessary for proper functioning of the immune system and are key mediators of inflammatory responses to pathogens. 1,2 Furthermore, NF-B activity is associated with cell proliferation, transformation, and tumor development. [3][4][5] One of its most important functions is the activation of an antiapoptotic gene expression program. [6][7][8] The NF-B/Rel family consists of 5 members (p50, p52, p65 [RelA], c-Rel, and RelB), which can form various homodimeric or heterodimeric complexes. NF-B is activated by the release from cytoplasmic IB proteins and subsequently translocates into the nucleus. 1,2,9 Activation is triggered by signal-induced phosphorylation of IB␣, IB, and IB⑀ at N-terminal serines, which target the inhibitors for rapid degradation by the proteasome. [10][11][12] The IB kinase (IKK) complex, containing 2 protein kinases, IKK␣ and IKK, is responsible for the inducible phosphorylation of IBs and is the initial point of convergence for most stimuli that activate 12 Evidence linking aberrant Rel/NF-B activity to oncogenesis has emerged in recent years. Chromosomal rearrangements of genes coding for Rel/NF-B factors have been observed in many human hematopoietic and solid tumors. Several human cancer cell types are characterized by persistent nuclear NF-B activity, as a result of constitutive activation of upstream signaling kinases or mutations inactivating IB subunits. 5 Consistently, the viral oncoprotein v-Rel has transforming capacity in vitro and in vivo, 13 and several oncogenic viruses, such as human T-cell leukemia virus type I and Epstein-Barr virus (EBV), activate NF-B as part of the transformation process. 14,15 Recently, we have discovered deregulated NF-B activation in The molecular basis of constitutive NF-B in H/RS is not completely understood. In some H/RS cell lines and in biopsy samples from patients with relapsed HD, mutations in the IB␣ gene may contribute to constitutive NF-B activation. These mutations produce nonfunctional or unstable IB␣ proteins, missing various portions of the ankyrin domain and the C-terminal region. [22][23][24][25][26] However, most HD cell lines and primary neoplastic cells lack mutations in the ib␣ gene, and constitutive NF-B activity could also be observed in cell lines with wild-type IB␣ alleles. 25 In all cases examined, IKKs were constitutively activated, resulting in rapid degradation of IB␣ proteins and indicating ongoing signal transduction. 25 Because HD is often associated with EBV, the EBV-encoded latent membrane protein-1 may activate NF-B in these cases by promoting IB␣ turnover. 27 However, constitutive IKK activation was also observed in EBV Ϫ cell lines. 25 Interestingly, H/RS cells strongly express CD30 and CD40, 2 members of the tumor necrosis factor (TNF) receptor family that both can activate NF-B. [28][29][30][31][32][33] From the Max Delbrü ck Center for Molecular Medicine; HepaVec...
