Akt Stimulates the Transactivation Potential of the RelA/p65 Subunit of NF-κB through Utilization of the IκB Kinase and Activation of the Mitogen-activated Protein Kinase p38*

By L. Madrid, Marty W. Mayo, J. Reuther, A. Baldwin. Journal of Biological Chemistry, 2001

857 citations recorded by the source corpus.

The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-κB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-κB has been controversial, with evidence supporting induction of nuclear translocation of NF-κB via activation of IκB kinase activity and/or the stimulation of the transcription function of NF-κB. Here we demonstrate that Akt targets the transactivation function of NF-κB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IκB kinase β activity and on the mitogen-activated protein kinase p38 (p38). Activation of RelA/p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-κB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1β to activate NF-κB is known to involve Akt, and we show here that IL-1β induces p38 activity in manner dependent on Akt and IκB kinase activation. Interestingly, activated Akt and the transcriptional co-activators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through IκB kinase and p38, induces the transcription function of NF-κB by stimulating the RelA/p65 transactivation subunit of NF-κB.

Subfields: Cancer Research, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/344d043476eaa5cc67a80e55749950b33c0b17c7

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The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. N. Perkins
2. S. Ghosh
3. T. Gilmore
4. Yves Pommier
5. Peng Huang
6. Peter Scheurich
7. A. Baldwin
8. G. Barber

In Immunology

1. N. Perkins
2. S. Ghosh
3. T. Abe
4. T. Gilmore
5. G. Barber
6. N. Holbrook
7. J. Martindale
8. H. Nakano

In Oncology

1. N. Perkins
2. S. Ghosh
3. Yves Pommier
4. Peng Huang
5. A. Baldwin
6. G. Barber
7. N. Holbrook
8. J. Martindale

Citations in the corpus

• IκBα and p65 Regulate the Cytoplasmic Shuttling of Nuclear Corepressors: Cross-talk between Notch and NFκB Pathways (2003, background): “…acid and thyroid hormone; TAD, transactivation domain; TNF- , tumor necrosis factor alpha; TSA, trichostatin A. © 2003 by The American Society for Cell Biology 491 phorylation (Zhong et al., 1998; Carter et al., 1999; Madrid et al., 2001; Sizemore et al., 2002) and acetylation (Chen et al., 2001).”
• Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. (2008, background): “We and others reported (Madrid et al. 2001; Sizemore et al. 2002) that Akt functions through IKK to promote the transactivation potential and phosphorylation (RelA) of NF- B. Akt is proposed to promote metastasis and angiogenesis through IKK in a manner that depends on NFB and -catenin activation…”
• Good cop, bad cop: the different faces of NF-κB (2006, background): “Interestingly, PI3K/PKB activity has also been shown to induce the p38 MAP kinase pathway.(41) In numerous systems, p38 MAP kinase has been shown to regulate NF-kB transcriptional activity without affecting its translocation to the nucleus.”
• Transient and Selective NF-κB p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by IκB Kinase β and Controls the Kinetics of p65 Nuclear Import 1 (2004, positive): “Because PKB/Akt is one of the activators of Cot (47) and the PI3K/ Akt pathway has been implicated in the stimulation of phosphorylation and trans activation by p65 (23, 48), we tested the impact of PKB/Akt on p65 serine 536 phosphorylation.”
• The Phosphorylation Status of Nuclear NF-ΚB Determines Its Association with CBP/p300 or HDAC-1 (2002, background): “However, NF- B heterodimers bind phosphorylation by casein kinase II and IKK (Bird et with greater affinity to most B sites on natural promotal., 1997; Madrid et al., 2001; Wang et al., 2000) plays ers (Kunsch et al.”
• Tumor necrosis factor signaling (2003, background): “constitutively active Akt (Myr-Akt) and in the other study TNF was used to induce transactivation of p65.(92,104) However, in the study of Sizemore et al.”
• Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-κB Activation through TBK1 (2014, background): “to be involved in NF- Bp65/RelA activation through IKK activation (17).”
• Redox Regulation of Cell Survival (2008, positive): “Under certain conditions, hydrogen peroxide is able to activate NF-(cid:2) B activity directly through phosphorylation/activation of IKK (144), or indirectly via MEKK-1 or Akt (196, 226).”
• Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks (2004, background): “AKT being one of the IKK kinases (Figures 3a and 4: #11; A1–3) (Ozes et al., 1999; Romashkova and Makarov, 1999), NF-kB activation is one of the mechanisms by which AKT enhances cell survival (Madrid et al., 2001) (see Figure 3 and the previous section).”
• Cellular response to oxidative stress: Signaling for suicide and survival * (2002, background): “Activation of PKC by phorbol ester protects nerve cells from oxidative glutamate toxicity by downregulating PKCd, activating ERK and JNK, and inactivating p38 (Maher, 2001).”