Nuclear NF-κB p65 Phosphorylation at Serine 276 by Protein Kinase A Contributes to the Malignant Phenotype of Head and Neck Cancer

Arun, Pattatheyil; Brown, Matthew S.; Ehsanian, Reza; Chen, Zhong; Waes, Carter Van

doi:10.1158/1078-0432.ccr-09-1352

Cited by 61 publications

(44 citation statements)

References 46 publications

(51 reference statements)

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“…Moreover, inhibition of PKA pathway by H89 could abolish the cAMP-mediated aromatase induction through up-regulating brca1 expression (44). Similar to our study, a number of previous reports support the possibility that PKA signaling contributes to the constitutive NF-B activation (45)(46)(47). In this study, we demonstrated that NF-B inhibitor BAY11-7082 repressed MDA-MB231 cell proliferation by blocking IKK, and PKA inhibitor H89 further augmented this inhibitory action (Fig.…”

Section: Discussionsupporting

confidence: 92%

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

Gao

Hibi

Cueno

et al. 2010

Journal of Biological Chemistry

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NF-B is an inducible transcriptional factor for the expression of multiple genes involved in immunoinflammatory responses, cell proliferation, and survival, thus playing crucial roles in the pathogenesis of many diseases, including cancer, leukemia, and autoimmune diseases (1-4). NF-B primarily exists as the heterodimer consisting of p65 and p50 in the cytoplasm and is sequestered by binding to its inhibitory protein IB (5). Upon signaling, such as by tumor necrosis factor ␣ (TNF␣), IB is phosphorylated and is followed by proteasomemediated degradation, which liberates NF-B to the nucleus thereby activating the target genes.PKA exists in the cytoplasm as an inactivated tetramer holoenzyme composed of dimer catalytic subunits and dimer regulatory subunits, which dissociate upon elevation of cAMP (6 -10). PKAc is also predominantly involved in the IB-NF-B complex in the cytoplasm, and IB sequesters PKAc by masking its catalytic domain (11). Following a variety of extracellular stimuli such as TNF␣, IB is phosphorylated by IKK 2 and degraded by the 26 S proteasome (12, 13). As a consequence, the p65/p50 heterodimer complex is liberated, and the catalytic center of PKAc is exposed, enabling activated PKAc to phosphorylate p65 at 15). This PKA-dependent phosphorylation of p65 facilitates the recruitment of transcription coactivator CBP and DNA binding activity of p65; therefore, activation of PKA augments NF-B-dependent gene expression, and PKAc signaling is considered to up-regulate . With regard to the role of PKAc in NF-B signaling, some claimed that cAMP-dependent PKA activation down-regulated NF-B-dependent transcription by changing its DNA binding ability (18,19), modifying the transactivation domain of p65 (20), or blocking the degradation of IB proteins (21,22).In our previous report, we identified AKIP1 as a novel p65-interacting protein (23). AKIP1 was initially found in breast cancer cells (24) in which it facilitated the nuclear translocation of PKAc (25). We found that AKIP1 appears to serve as a molecular bridge between p65 and PKAc, promoting their interaction and subsequent p65 phosphorylation at Ser-276, thus enhancing NF-B signaling (23). Because NF-B is constitutively activated in some breast cancer cells, endowing them with resistance to apoptosis (26 -28), we hypothesized that the effect of PKA in NF-B cascade is associated with AKIP1 and could be modulated by AKIP1 in a cell type-dependent fashion.In this study, we further investigate the role of PKA in regulating NF-B-dependent transcription in various cell lines with different expression levels of endogenous AKIP1. We provide evidence that in minimal AKIP1-expressing cell lines, elevation of cAMP decreased p65-PKA binding and p65 phosphorylation at Ser-276, which eventually leads to down-regulation of the NF-B-dependent transcription. In contrast, in breast cancer cell lines MDA-MB231 and MCF7 with high AKIP1 expression, the PKA-activating agents increased p65-PKA binding and its phosphorylation and up-regulated the NF-B-dependent transcriptio...

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Section: Discussionsupporting

confidence: 92%

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

Gao

Hibi

Cueno

et al. 2010

Journal of Biological Chemistry

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“…For example, phosphorylation of NF-κB at Ser276 by PKA stimulates NF-κB transcriptional activity by promoting the interaction of NF-κB with the coactivator CBP/p300 (62). NF-κB p65 phosphorylation at Ser276 by PKA activates NF-κB and contributes to the malignant phenotype of head and neck cancer (84). It has been also shown that PKA-Cα activates NF-κB signaling via phosphorylating p65 at Ser276 in an IKKβ-dependent but cAMP-independent manner (61).…”

Section: (E-h) Beas-2b Cells Were Transfected With Sirna (E and F) Ormentioning

confidence: 99%

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Susuki-Miyata

Miyata

Lee

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit β (PKA-Cβ) and nuclear factor-κB (NF-κB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cβ phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor.PDE4B | Roflumilast | nontypeable Haemophilus influenzae | PKA-Cβ | p65

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“…ICAM1 gene promoters contain several NF-kB response elements (Stade et al 1990). Most importantly, PKA has been reported to phosphorylate the p65 subunit of NF-kB, which contributed to the binding of NF-kB to the ICAM1 gene promoter (Arun et al 2009). To address the question whether NF-kB participated in Ucn1-induced ICAM1 regulation, we used an NF-kB inhibitor, PDTC.…”

Section: Pka-creb Participated In the Signaling Events Leading To Indmentioning

confidence: 99%

Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs

Wan¹,

Liu²,

Li³

et al. 2014

Journal of Molecular Endocrinology

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Urocortin (Ucn1), a member of the corticotrophin-releasing hormone (CRH) family, has been reported to participate in inflammation. The increased expression of intercellular adhesion molecule 1 (ICAM1) plays important roles in inflammation and immune responses. Our previous results demonstrated that Ucn1 significantly enhanced the expression of ICAM1. However, the underlying mechanisms are still unknown. The purpose of this study is to investigate the detailed mechanisms of Ucn1-induced upregulation of ICAM1. Here, we characterized the mechanisms of Ucn1 usage to regulate ICAM1 expression in human umbilical vein endothelial cells (HUVECs). Our data revealed that Ucn1 increased ICAM1 and cyclooxygenase 2 (COX2) expressions in a time-dependent manner via CRH receptor 2 (CRHR2). In addition, COX2 was involved in ICAM1 upregulation. Furthermore, Ucn1 could increase the expression and phosphorylation of cytosolic phospholipases A2 (cPLA2) in a time-dependent manner via CRHR2 and CRHR1. Moreover, ablation of cPLA2 by the inhibitor pyrrophenone or siRNA attenuated the ICAM1 increase induced by Ucn1. In addition, nuclear factor kB (NF-kB) was activated, indicated by the increase in nuclear p65NF-kB expression and phosphorylation of p65NF-kB, depending on cPLA2 and CRHR2 activation. Pyrrolidinedithiocarbamic acid, an inhibitor of NF-kB, abolished the elevation of ICAM1 but not COX2. Also, Ucn1 increased the production of prostaglandin E 2 (PGE 2 ) which further activated protein kinase A (PKA)-CREB pathways dependent of cPLA2 via CRHR2. Moreover, the increase in NF-kB phosphorylation was not affected by the selective COX2 inhibitor NS-398 or the PKA inhibitor H89. In conclusion, these data indicate that Ucn1 increase the ICAM1 expression via cPLA2-NF-kB and cPLA2-COX2-PGE 2 -PKA-CREB pathways by means of CRHR2.

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Nuclear NF-κB p65 Phosphorylation at Serine 276 by Protein Kinase A Contributes to the Malignant Phenotype of Head and Neck Cancer

Cited by 61 publications

References 46 publications

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs

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