Tumor Necrosis Factor α-induced Phosphorylation of RelA/p65 on Ser529 Is Controlled by Casein Kinase II

Wang, Dan; Westerheide, Sandy D.; Hanson, Julie L.; Baldwin, Albert S.

doi:10.1074/jbc.m001358200

Cited by 413 publications

(328 citation statements)

References 61 publications

Supporting

Mentioning

311

Contrasting

Unclassified

Order By: Relevance

“…4 Cytoplasmic NF-AT (cytoplasmic nuclear factor of activated T cells (NF-Atc)) is phosphorylated by CKII and translocated into the nucleus. 5 RelA (p65) is phosphorylated at multiple serine residues such as Ser 529 , 6,7 Ser 536 , 8 and Ser 276 9 by CKII, IkB kinase (IKK), and protein kinase A (PKA)/mitogen and stress-activated protein kinase (MSK), respectively. PKA catalytic subunit binds with IkBa of NF-kB/IkB complex and remains inactive.…”

mentioning

confidence: 99%

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

View full text Add to dashboard Cite

The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P 3 -25) is known to possess antibacterial, anti-fungal, anti-tubercular, and local anesthetic activities. We studied the anti-tumorigenic activity of P 3 -25 and the role of nuclear transcription factor kappaB (NF-jB) in this process. In constitutive NF-jB-expressing cells, treatment with P 3 -25 inhibited the expression of NF-jB-dependent reporter gene, adhesion molecules, and cyclooxygenase. It downregulated phosphorylation of p65 by inhibiting upstream kinases, such as protein kinase A and casein kinase II, but did not alter NF-jB DNA-binding activity. Alone, P 3 -25 induced apoptosis in NF-jB-expressing and doxorubicin-resistant breast cancer cells, and in the presence of other chemotherapeutic agents, it potentiated apoptosis. Overall, our results suggest that P 3 -25 exerts antitumorigenic activity by inhibiting phosphorylation of p65, the transcriptionally active subunit of NF-jB by inhibiting its upstream kinases, and potentiates apoptosis mediated by chemotherapeutic agents. These results suggest novel approaches for designing of anticancer drugs for combination chemotherapy.

show abstract

mentioning

confidence: 99%

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Several studies have shown that p65 can be phosphorylated at Ser-276, Ser-529, and Ser-536 by protein kinase A, casein kinase II, and IKK, respectively. 27,31,32 This phosphorylation was suggested to increase the transactivation potential of NF-kB. In our study, TAK1-DN did not reduce the RANKL-induced phosphorylation and degradation of IkB (Figure 7a), indicating that RANKL stimulation of IKK was not likely to be inhibited by this retroviral transduction.…”

Section: Discussionmentioning

confidence: 57%

Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL

et al. 2006

View full text Add to dashboard Cite

Osteoclast (Oc) differentiation is fundamentally controlled by receptor activator of nuclear factor kappaB ligand (RANKL). RANKL signalling targets include mitogen-activated protein kinases (MAPKs), nuclear factor kappaB (NF-jB), and nuclear factor of activated T cells (NFAT)c1. In this study, we found that p38 MAPK upstream components transforming growth factor-beta-activated kinase 1 (TAK1), MKK3, and MKK6 increased by RANKL in an early stage of osteoclastogenesis from primary bone marrow cells, which led to enhanced p38 activation. Retroviral transduction of dominant-negative (DN) forms of TAK1 and MKK6, but not that of MKK3, reduced Oc differentiation. Transduction of TAK1-DN and MKK6-DN and treatment with the p38 inhibitor SB203580 attenuated NFATc1 induction by RANKL. TAK1-DN, MKK6-DN, and SB203580, but not MKK3-DN, also suppressed RANKL stimulation of NF-jB transcription activity in a manner dependent on p65 phosphorylation on Ser-536. These results indicate that TAK1 and MKK6 constitute the p38 signalling pathway to participate to Oc differentiation by RANKL through p65 phosphorylation and NFATc1 induction, and that MKK6 and MKK3 have differential roles in osteoclastogenesis from bone marrow precursors.

show abstract

“…CK2 forms a heterocomplex composed of two catalytic a subunits and two regulatory subunits (9). It was reported that CK2 phosphorylates p65 (10)(11)(12), an action critical for NF-kB-mediated transcription (13,14), although a detailed molecular mechanism of how CK2 regulates the transcription has not been shown.…”

Section: B Reakpoint Cluster Region (Bcr) Protein Is a Unique Kinasementioning

confidence: 99%

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Meng

Jiang

Atsumi

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.

show abstract

Tumor Necrosis Factor α-induced Phosphorylation of RelA/p65 on Ser529 Is Controlled by Casein Kinase II

Cited by 413 publications

References 61 publications

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Contact Info

Product

Resources

About