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I?B kinase ? (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor ?B (NF?B) signaling.

ABSTRACT: Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKK?), the critical activating kinase in canonical (NF?B) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKK? and K171T IKK? represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation loop phosphorylation-dependent kinase result in constitutive activation. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKK? contributes to lymphomagenesis.

SUBMITTER: Kai X

PROVIDER: S-EPMC4175336 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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IκB kinase β (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling.

Kai Xin X Chellappa Vasant V Donado Carlos C Reyon Deepak D Sekigami Yurie Y Ataca Dalya D Louissaint Abner A Mattoo Hamid H Joung J Keith JK Pillai Shiv S

The Journal of biological chemistry 20140808 39

Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKKβ), the critical activating kinase in canonical (NFκB) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKKβ and K171T IKKβ represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predict ...[more]

PMID: 25107905

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Project description:Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug resistance in multiple myeloma.

Dataset Information

I?B kinase ? (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor ?B (NF?B) signaling.

Publications

IκB kinase β (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling.

Similar Datasets

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