The generation of nfkb2 p52: mechanism and efficiency

Heusch, Marina; Li, Lin; Geleziunas, Romas; Greene, Warner C.

doi:10.1038/sj.onc.1203022

Cited by 108 publications

(87 citation statements)

References 32 publications

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“…2, B and E), suggesting that similar repression of p52 and RelB activities can be achieved. Constitutive processing generates a low level of p52 in the cell (49,50), and production of p52 is greatly enhanced by stimulation of a subset of cytokines (14). Deregulation of nfkb2 genes also results in malignancy (51,52), and inhibition of abnormal p52 homodimer activity may be of significant importance.…”

Section: Discussionmentioning

confidence: 99%

A p105-based Inhibitor Broadly Represses NF-κB Activities

Kobayashi

2004

Journal of Biological Chemistry

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An I B␣-based NF-B super repressor (sr) has been used widely for studying genes regulated by NF-B transcription factors. Repression of NF-B by I B␣(sr) also facilitates tumor necrosis factor ␣-induced apoptosis in the cell. However, I B␣ primarily targets RelA and cRel-containing complexes, leaving other NF-B/Rel protein complexes, such as p50 and p52 homodimers, and RelB heterodimers uninhibited. Because these atypical NF-B complexes also contribute to gene regulation and are activated in pathological conditions, broad inhibition of all NF-B species is of significant pharmacological and clinical interests. We have designed, generated, and tested a p105-based NF-B super repressor. We showed that p105(sr), which no longer generates p50 and undergoes signal-induced degradation, effectively inhibits all NF-B activities. In addition, we also demonstrated that p105(sr) significantly enhances tumor necrosis factor ␣-mediated killing of MT1/2 skin papilloma cells where p50 homodimer activity is elevated. Our results suggest that p105(sr) is a broader range and effective NF-B super repressor and can potentially be used in cells where a noncanonical NF-B activity is dominant or multiple NF-B activities are activated.Nuclear factor B (NF-B) 1 is a latent dimeric complex sequestered in the cytoplasm by its inhibitor I B and is activated to engage transcription in the nucleus by various stimuli (1). In normal physiological conditions such activation is transient, because of autoregulatory mechanisms (2, 3). However, this family of transcription factors is constitutively activated in many types of cancer cell and is thought to regulate anti-apoptosis factors that aid survival of the cancer cells (4 -8). Chemotherapy reagents induce death of cancer cells but also activate NF-B pathways. Therefore, activation of NF-B is a contributing factor of chemoresistance. Introduction of an I B␣-based NF-B super repressor (sr) into cancer cells has not only enhanced stimuli-induced apoptosis (9 -11) but also facilitated systematic identification of genes regulated by NF-B that may contribute to the malignancy and progression of the tumor (12). Activation of prototypic NF-B requires degradation of I Bs, and the prerequisite of the process is stimuli-induced phosphorylation of I Bs by the I B kinase-constituted signalsome (13). I B␣(sr) was generated by either mutating serine 32 and 36, which are the targets of the I B kinases or deleting the Nterminal portion of I B␣ that harbors these targets. I B␣(sr) suppresses stimuli-induced NF-B activation, because the inhibitor now cannot be phosphorylated and therefore will not be subjected to immediate degradation, and the bound NF-B subunits will not be released into the nucleus.Although in most normal and cancer cells, the NF-B activity detected is that of prototype p50/RelA heterodimer, atypical/ noncanonical NF-B species also play significant roles in gene regulations (14). For example, the RelB/p52 complex plays a key role in B cell development (14). It has also been observed that NF-B p50 h...

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Section: Discussionmentioning

confidence: 99%

A p105-based Inhibitor Broadly Represses NF-κB Activities

Kobayashi

2004

Journal of Biological Chemistry

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“…to 52 kDa form (Heusch et al, 1999). As Btz could be affecting this activation, we analyzed the processing and activation of NF-kB2 in our experimental system by western blot.…”

Section: Btz Prevents the Activation Of Nf-kbmentioning

confidence: 99%

Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells

et al. 2010

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“…Recent data suggest that the Tpl-2 protein kinase can induce phosphorylation and degradation of NF-kB1 p105, resulting in generation of active nuclear NF-kB (Belich et al, 1999). p50 NF-kB-1 and p52 NF-kB-2 are also generated by a direct co-translational processing event, in which the nascent, ankyrin-containing, precursor proteins are subjected to proteasomal cleavage during translation, resulting in formation of p50 and p52, independent of production of the full-length gene products (Heusch et al, 1999;Lin et al, 1998).…”

Section: Introductionmentioning

confidence: 99%