Histone H3 phosphorylation by IKK-α is critical for cytokine-induced gene expression

Yamamoto, Yumi; Verma, Udit; Prajapati, Shashi; Kwak, Youn-Tae; Gaynor, Richard B.

doi:10.1038/nature01576

Cited by 556 publications

(569 citation statements)

References 29 publications

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“…IKKα is a component of the IKK complex. 5 In addition to its cytoplasmic functions where it controls the activation of both classical and alternative NF-κB pathways, 6,[9][10][11][12] IKKα can function as a nuclear protein kinase, [33][34][35] and nuclear IKKα plays important roles in prostate cancer progression and metastasis. 13,14 In the present study we have shown that IKKα controls the biogenesis of a group of miRNA, including miR-196a.…”

Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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Radioresistance is a major obstacle in successful clinical cancer radiotherapy, and the underlying mechanisms are not clear. Here we show that IKKα-mediated miR-196a biogenesis via interaction with Drosha regulates the sensitivity of nasopharyngeal carcinoma (NPC) cells to radiotherapy. Phosphorylation of IKKα at T23 site (p-IKKαT23) promotes the binding of IKKα to Drosha that accelerates the processing of miR-196a primary transcripts, leading to increased expressions of both precursor and mature miR-196a. Dephosphorylation of p-IKKαT23 downregulates miR-196a expression and promotes the resistance of NPC cells to radiation treatment. The miR-196a mimic suppresses while its inhibitor promotes the resistance of NPC to radiation treatment. Importantly, the expression of p-IKKαT23 is positively related to the expression of miR-196a in human NPC tissues, and expression of p-IKKαT23 and miR-196a is inversely correlated with NPC clinical radioresistance. Thus, our studies establish a novel mechanistic link between the inactivation of IKKαT23-Drosha-miR-196a pathway and NPC radioresistance, and de-inactivation of IKKαT23-Drosha-miR-196a pathway would be an efficient way to restore the sensitivity of radioresistant NPC to radiotherapy.

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Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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“…Its major role in regulating the NF-kB pathway involves the signal-dependent phosphorylation of p100, a step that is necessary to initiate the proteolytic processing of p100 required to generate p52-containing dimers (Hayden and Ghosh, 2004), which among other things are essential for the normal development of lymphoid organs. During inflammation, IKKa also serves a nuclearspecific role in NF-kB-dependent gene expression by modifying chromatin structure through phosphorylation of histones (Anest et al, 2003;Yamamoto et al, 2003). In contrast to these NF-kB-dependent roles in the immune system, in the skin IKKa serves an NF-kB-independent function.…”

Section: Ikkamentioning

confidence: 99%

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

et al. 2006

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The nuclear factor-jB (NF-jB) signalling pathway serves a crucial role in regulating the transcriptional responses of physiological processes that include cell division, cell survival, differentiation, immunity and inflammation. Here we outline studies using mouse models in which the core components of the NF-jB pathway, namely the IjB kinase subunits (IKKa, IKKb and NEMO), the IjB proteins (IjBa, IjBb, IjBe and Bcl-3) and the five NF-jB transcription factors (NF-jB1, NF-jB2, c-Rel, RelA and RelB), have been genetically manipulated using transgenic and knockout technology.

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“…An interesting aspect of H3 phosphorylation is its regulation by signal transduction pathways. Phosphorylation of histone H3 at serine 10 has been shown to be increased in mammalian interphase nuclei by the MAP kinase [9], protein kinase A (PKA) [10,11], and NF-κB-cytokine signaling pathways [12,13]. In each case increased H3 phosphorylation was found to occur at particular genes activated by these pathways which suggests a role in regulation of gene expression [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Phosphorylation of histone H3 at serine 10 has been shown to be increased in mammalian interphase nuclei by the MAP kinase [9], protein kinase A (PKA) [10,11], and NF-κB-cytokine signaling pathways [12,13]. In each case increased H3 phosphorylation was found to occur at particular genes activated by these pathways which suggests a role in regulation of gene expression [11][12][13][14][15]. Kinases shown to play important roles in the regulation of H3 phosphorylation at serines 10 and 28 include MSK1/2 [16,17], IKKα [12,13] and aurora kinases (mitotic phosphorylation) [18].…”

Section: Introductionmentioning

confidence: 99%

“…In each case increased H3 phosphorylation was found to occur at particular genes activated by these pathways which suggests a role in regulation of gene expression [11][12][13][14][15]. Kinases shown to play important roles in the regulation of H3 phosphorylation at serines 10 and 28 include MSK1/2 [16,17], IKKα [12,13] and aurora kinases (mitotic phosphorylation) [18].…”

Section: Introductionmentioning

confidence: 99%

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cAMP signaling induces rapid loss of histone H3 phosphorylation in mammary adenocarcinoma-derived cell lines

Rodriguez-Collazo

Snyder

Chiffer

et al. 2008

Experimental Cell Research

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The phosphorylation of histone H3 is known to play a role in regulation of transcription as well as preparation of chromosomes for mitosis. Various signaling cascades induce H3 phosphorylation, particularly at genes activated by these pathways. In this study we show that signaling can also have the opposite effect. Activators of cAMP signaling induce a rapid and potent loss of H3 phosphorylation. This effect is not mediated through a cAMP metabolite since a membranepermeable form of AMP had no effect on H3 phosphorylation and a phosphodiesterase-resistant cAMP analog efficiently reduced it. cAMP is also the likely regulator of H3 phosphorylation under physiological conditions since only supra-pharmacological doses of cGMP induce the loss of H3 phosphorylation. The loss of phosphorylation is specific for histone H3 since we do not observe drastic losses in total phosphorylation of other histones. In addition, other H3 modifications are unaffected with the exception of lysine 9 methylation, which is elevated. Analysis of cell growth and cell cycle show that cAMP signaling inhibits cell growth and arrests cells at both G1 and G2/M. Similar effects of cAMP signaling on H3 phosphorylation are observed in a variety of mammary adenocarcinoma-derived cell lines. In syngeneic human breast derived cell lines, one diploid and non-transformed, the other derived from a ductal carcinoma, the loss of H3 phosphorylation is significantly more sensitive to cAMP concentration in the transformed cell line.

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Histone H3 phosphorylation by IKK-α is critical for cytokine-induced gene expression

Cited by 556 publications

References 29 publications

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

cAMP signaling induces rapid loss of histone H3 phosphorylation in mammary adenocarcinoma-derived cell lines

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