Notch1 augments NF-κB activity by facilitating its nuclear retention

Shin, Hyun Mu; Minter, Lisa M.; Cho, Ok Hyun; Gottipati, Sridevi; Fauq, Abdul H.; Golde, Todd E.; Sonenshein, Gail E.; Osborne, Barbara A.

doi:10.1038/sj.emboj.7600902

Cited by 276 publications

(276 citation statements)

References 48 publications

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“…mechanism could be the direct association of activated Notch1 with NF-B components in the nucleus, as indicated by a very recent report for T cells (Shin et al 2006). Besides NF-B-binding sites, both mouse and human ⌬Np63 promoters contain several interferon-responsive elements, with a potentially significant similarity with the ␤-interferon enhancer, where a synergistic multiprotein complex is formed (Thanos and Maniatis 1995) by NF-B subunits and IRF3/IRF7 proteins, two key downstream mediators of the interferon response (Servant et al 2002;Zhang and Pagano 2002).…”

Section: Discussionmentioning

confidence: 92%

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

336

411

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Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Normal tissue homeostasis is determined by a complex interplay between developmental signals and other cell regulatory pathways. Notch cell surface receptors and their ligands belonging to the Delta and Serrate/Jagged families play a crucial role in cell fate determination and differentiation, functioning in a cell-and context-specific manner (Artavanis-Tsakonas et al. 1999). In mammalian cells, Notch activation is generally thought to maintain stem cell potential and inhibit differentiation, thereby promoting carcinogenesis (Artavanis-Tsakonas et al. 1999). However, in specific cell types such as keratinocytes, increased Notch activity causes exit from the cell cycle and commitment to differentiation (Lowell et al. 2000;Rangarajan et al. 2001;Nickoloff et al. 2002), whereas down-modulation or loss of Notch1 function promotes carcinogenesis (Talora et al. 2002;Nicolas et al. 2003).In the human epidermis, localized expression of the Notch-ligand Delta in putative "stem cells" has been proposed to induce commitment of neighboring Notch1-expressing keratinocytes to a "transit-amplifying" phenotype, through a negative feedback mechanism of lateral inhibition (Lowell et al. 2000). On the other hand, in both mouse and human epidermis, Jagged 1/2, Notch1, and Notch2 are coexpressed in differentiating keratinocytes of the supra-basal layers, consistent with a positive feedback loop between these molecules that serves to reinforce and synchronize Notch activation with differentiation (Luo et al. 1997;Rangarajan et al. 2001;Nickoloff et al. 2002).The best characterized "canonical" pathway of Notch activation involves proteolytic cleavage and translocation of the cytoplasmic domain of the receptor to the nucleus, where it associates with the DNA-binding protein RBP-J (CBF-1, CSL), converting it from a repressor

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Section: Discussionmentioning

confidence: 92%

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

336

411

View full text Add to dashboard Cite

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“…Thus, we used NIC constructs modified for nuclear retention by an additional nuclear localization sequence (GFP-N1 IC-NLS ) or a nuclear export signal (GFP-N1 IC-NES ) to increase or decrease nuclear retention, respectively. 28,29 An additional NLS (GFP-N1 IC-NLS ) resulted in a loss of NIC-mediated antiapoptotic activity ( Figure 7a) compared with cells expressing NIC (Po0.001). However, the GFP-N1 IC-NES construct tested in the same experiments was as effective as NIC (P ¼ 0.64) in protecting cells from neglect-induced death (Figure 7a).…”

Section: Resultsmentioning

confidence: 99%

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells

et al. 2009

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The regulation of cellular metabolism and survival by trophic factors is not completely understood. Here, we describe a signaling cascade activated by the developmental regulator Notch, which inhibits apoptosis triggered by neglect in mammalian cells. In this pathway, the Notch intracellular domain (NIC), which is released after interaction with ligand, converges on the kinase mammalian target of rapamycin (mTOR) and the substrate-defining protein rapamycin independent companion of mTOR (Rictor), culminating in the activation of the kinase Akt/PKB. Biochemical and molecular approaches using site-directed mutants identified AktS473 as a key downstream target in the antiapoptotic pathway activated by NIC. Despite the demonstrated requirement for Notch processing and its predominant nuclear localization, NIC function was independent of CBF1/RBP-J, an essential DNA-binding component required for canonical signaling. In experiments that placed spatial constraints on NIC, enforced nuclear retention abrogated antiapoptotic activity and a membrane-anchored form of NIC-blocked apoptosis through mTOR, Rictor and Akt-dependent signaling. We show that the NIC-mTORC2-Akt cascade blocks the apoptotic response triggered by removal of medium or serum deprivation. Consistently, membrane-tethered NIC, and AktS473 inhibited apoptosis triggered by cytokine deprivation in activated T cells. Thus, this study identifies a non-canonical signaling cascade wherein NIC integrates with multiple pathways to regulate cell survival.

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“…DsRedp50 and EGFP-c_Rel were gifts from Dr. Barbara A. Osborne (16). HA-tagged IB␣, both wild-type and superrepressor (SR) S32A/S36A mutant, under the control of ␤-actin promoter in pRC vector, were described previously (17).…”

Section: Methodsmentioning

confidence: 99%

The Mastermind-like 1 (MAML1) Co-activator Regulates Constitutive NF-κB Signaling and Cell Survival

Jin

Shen

Lin

et al. 2010

Journal of Biological Chemistry

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Nuclear factor-B (NF-B)-based signaling regulates diverse biological processes, and its deregulation is associated with various disorders including autoimmune diseases and cancer. Identification of novel factors that modulate NF-B function is therefore of significant importance. The Mastermind-like 1 (MAML1) transcriptional co-activator regulates transcriptional activity in the Notch pathway and is emerging as a co-activator of other pathways. In this study, we found that MAML1 regulates NF-B signaling via two mechanisms. First, MAML1 coactivates the NF-B subunit RelA (p65) in NF-B-dependent transcription. Second, MAML1 causes degradation of the inhibitor of NF-B (IB␣). Maml1-deficient mouse embryonic fibroblasts showed impaired tumor necrosis factor-␣ (TNF␣)-induced NF-B responses. Moreover, MAML1 expression level directly influences cellular sensitivity to TNF␣-induced cytotoxicity. In vivo, mice deficient in the Maml1 gene exhibited spontaneous cell death in the liver, with a large increase in the number of apoptotic hepatic cells. These findings indicate that MAML1 is a novel modulator for NF-B signaling and regulates cellular survival. Nuclear factor-B (NF-B)2 signaling regulates diverse biological responses, including cell proliferation, survival, inflammation, and immunity (for review, see 1-4). Deregulated NF-B signaling is associated with many disease states such as AIDS, asthma, arthritis, cancer, diabetes, muscular dystrophy, stroke, and viral infection.NF-B consists of homo-or heterodimers of members of the Rel family: RelA (p65), RelB, c-Rel, p105 and its processing product p50, and p100 and its processing product p52. These proteins contain a Rel homology domain, a conserved 300-amino acid domain within their N termini that is responsible for DNA binding and homo-or heterodimerization. The common active forms of NF-B are RelA/p50 or RelA/p52 heterodimers. In its inactive state, NF-B remains sequestered in the cytoplasm by members of the inhibitor IB family. Although the IB family consists of IB␣, ␤, ␥ (p105), ␦ (p100), ⑀ and Bcl-3, the best studied and major IB protein is IB␣. NF-B-based signaling results from a variety of stimuli, including T cell receptor signals, cytokines, and viral and bacterial products. In the canonical pathway, an IB kinase (IKK) complex is activated upon response to these stimuli, and two kinases in this complex, IKK␣ and IKK␤, phosphorylate IB. Phosphorylation triggers IB for ubiquitination by the Skp/Cullin/F-box-containing ubiquitin ligase complex, leading to the degradation of IB by the 26 S proteasome. NF-B subsequently becomes liberated from its interaction with IB, rapidly translocates to the nucleus, and binds to its cognate DNA-binding site in the promoter or enhancer regions of specific NF-B target genes. Thus, the result of NF-B activation triggered from a myriad of cellular activators is highly regulated gene expression.The biological and pathogenic importance of NF-B signaling emphasizes the need to control its action tightly, both physiologically and therapeu...

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Notch1 augments NF-κB activity by facilitating its nuclear retention

Cited by 276 publications

References 48 publications

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells

The Mastermind-like 1 (MAML1) Co-activator Regulates Constitutive NF-κB Signaling and Cell Survival

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