Overexpressed NF-κB–inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells

Abstract

The nuclear factor-B (NF-B) transcription factors play important roles in cancer development by preventing apoptosis and facilitating the tumor cell growth. However, the precise mechanisms by which NF-B is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-B-inducing kinase (NIK) is overexpressed at the pretranslational IntroductionThe nuclear factor-B (NF-B) transcription factors are known to regulate the expression of a wide range of genes involved in development, immune responses, apoptosis, and carcinogenesis as dimers of the REL family members, RelA, RelB, c-Rel, p50, and p52. 1 The p50 and p52 proteins are generated by proteasomemediated processing of their precursors, p105 and p100, respectively. In resting cells, Rel proteins are sequestered in the cytoplasm through their interactions with the ankyrin repeats of the inhibitory proteins IB␣, -␤, and -⑀, as well as the precursor proteins p105 and p100. On stimulation, signals converge at the multiprotein IB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK1/␣ and IKK2/␤, and the scaffolding proteins, NF-B essential modulator (NEMO, also known as IKK␥) and ELKS. 2 Phosphorylation by the IKK complex of specific serine residues on the IB or precursor proteins results in their poly-ubiquitination and proteasome-dependent degradation or processing. 2 Released NF-B then translocates to the nucleus and regulates expression of target genes.NF-B signaling pathways are largely classified as either canonical or noncanonical based on the stimuli and targets of the IKK complex. 2 Canonical activation is induced by stimuli, such as tumor necrosis factor-␣ (TNF␣) and interleukin-1␤, and involves NEMO-and IKK2/␤-dependent phosphorylation and the subsequent degradation of IB proteins. Noncanonical NF-B pathways are activated after the stimulation of a range of TNF receptor family members, such as B-cell activating factor belonging to the TNF family (BAFF) receptor, lymphotoxin-␤ receptor, Fn14 and CD40, and direct NF-B-inducing kinase (NIK)-and IKK1/␣-dependent phosphorylation and subsequent processing of p100, leading to activation of NF-B complexes containing RelB. 2,3 Of note in this context, the noncanonical pathways operate in a delayed fashion and are sensitive to protein synthesis inhibition. 4,5 Compared with the mechanisms underlying the transduction of ligand-induced signaling to NF-B activation, much less is known about how NF-B is constitutively activated in a variety of cancer cells. 6 Constitutively high NF-B activity has typically been demonstrated in human hematopoietic cancer cells, including adult T-cell leukemia (ATL), Hodgkin lymphoma, and multiple myeloma cells. 7,8 We have previously reported the aberrant expression of p52 in ATL and Hodgkin Reed-Sternberg (H-RS) cells that do not express viral regulatory proteins, such as Tax of the human T-cell leukemia virus or latent membrane protein 1 of the Epstein-Barr virus. 9,10 In addition, IKK activation in ATL and H-RS c...

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

“…In support for a role of this pathway in lymphomagenesis, NIK is overexpressed in some cases of T-cell leukaemias and in Hodgkin's lymphomas that do not express any oncogenic viral proteins (Saitoh et al, 2008). Levels of p52 are also increased in those NIK overexpressing haematological disorders and levels of MMP9 are decreased on NIK depletion through RNAi interference in these cells (Saitoh et al, 2008). Thus, these data, combined with our report, suggest that MMP9 is a direct target gene of the NIK-and p100/p52-dependent signalling cascade.…”

Zinc-finger antiviral protein mediates retinoic acid inducible gene I–like receptor-independent antiviral response to murine leukemia virus

“…Primary MEFs were prepared from pregnant female mice on embryonic day 13.5, as described previously (4). To prepare bone marrow-derived dendritic cells, mouse bone marrow cells were cultured in the presence of 10 ng/mL GM-CSF (PeproTech) for 6 d, during which time the culture medium was replaced with medium containing GM-CSF every 2 d. The 293T cells have been described previously (46). Replication-competent MLV was produced by 293T cells transfected with pMLV-48.…”

Non-canonical NF-κB signaling pathway

“…As will be discussed below, HTLV Tax protein activates non-81 npg canonical NF-κB via a NIK-independent mechanism. However, the deregulation of NIK may be important for constitutive non-canonical NF-κB activation in ATL cells with low or undetectable levels of Tax [96].…”

“…It has been shown that the level of NIK mRNA is upregulated in adult T-cell leukemia (ATL) and Hodgkin Reed-Sternberg cells [96]. ATL is an acute T-cell malignancy caused by infection of the human T-cell leukemia virus type 1 (HTLV1).…”