The tumor suppressor protein menin interacts with NF-κB proteins and inhibits NF-κB-mediated transactivation

Heppner, Christina; Bilimoria, Karl Y.; Agarwal, Sunita K.; Kester, Mary Beth; Whitty, Leslie J.; Guru, Siradanahalli C.; Chandrasekharappa, Settara C.; Collins, Francis S.; Spiegel, Allen M.; Marx, Stephen J.; Burns, A. Lee

doi:10.1038/sj.onc.1204529

Cited by 224 publications

(155 citation statements)

References 37 publications

(36 reference statements)

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“…Additionally, the tumor suppressor CYLD blocks NF-kB and Bcl-3 activation through its deubiquitinating activity (Kovalenko et al, 2003;Trompouki et al, 2003;Massoumi et al, 2006). Moreover, the tumor suppressor menin, which is mutated/deleted in parathyroid tumors, was reported to bind and suppress NF-kB activation (Heppner et al, 2001). Regarding the tumor suppressor p53, it was reported that p53 generally inhibits NF-kB function, and vice versa (Webster and Perkins, 1999); however, more complex relationships between p53 and NF-kB have emerged (see below).…”

Section: Inhibition Of Nf-jb By Tumor Suppressorsmentioning

confidence: 99%

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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Section: Inhibition Of Nf-jb By Tumor Suppressorsmentioning

confidence: 99%

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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“…Menin has been shown specifically interacts with JunD but not with other members of Jun family (c-Jun, JunB), as their interactions are mediated through the far N-terminal region of JunD that is missing in c-Jun and JunB (Aggarwal et al, 1999). In addition to JunD, Menin is also known to interact with other transcription factors, including NF-κB, Smad3, and Pem, implicating a general role of Menin in regulating transcription (Heppner et al, 2001;Kaji et al, 2001;Lemmens et al, 2001). Menin is known to repress JunD-activated transcription.…”

Section: Menin Represses Jund Transcriptional Activity In Protein Kinmentioning

confidence: 99%

Menin represses JunD transcriptional activity in protein kinase Cθ-mediated Nur77 expression

Kim¹,

Lee²,

Kim³

et al. 2005

Exp Mol Med

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TCR signaling leading to thymocyte apoptosis is mediated through the expression of the Nur77 family of orphan nuclear receptors. It has been shown that the Nur77 promoter is activated by at least two signaling pathways, one mediated by calcium and the other by protein kinase C (PKC). MEF2D has been known to regulate Nur77 expression in a calciumdependent manner. The mechanism by which calcium regulates MEF2D is through dissociation of calcium-sensitive MEF2 corepressors (Cabin1/ HDACs, HDAC4/5) and the association with calcineurin-activated transcription factor NF-AT and the coactivator p300. However, little is known about how PKC activates the Nur77 promoter. Herein, we report that PKC targets AP-1 like response element in the Nur77 promoter where JunD constitutively binds. PKCθ triggers mitogen-activated protein kinaseinediated phosphorylation of JunD, and increases transcriptional activity of JunD, cooperatively with p300. Menin is identified as the transcriptional corepressor for JunD via recruitment of mSin3-istone deacetylases. In fact, Menin represses PKCθ/ p300-mediated transcriptional activity of JunD in T cell. Its dynamic regulation of histone modifiers with JunD is responsible for PKCθ-synergistic effect on Nur77 expression in T cell.

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“…Furthermore, Menin inactivation by antisense RNA antagonizes cell growth inhibition mediated by TGF-b (Kaji et al, 2001). Conversely, Menin interacts with the AP-1 transcription factor JunD and with NF-kB proteins and represses both NF-kB-mediated and JunD-dependent transcription Gobl et al, 1999;Heppner et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation

et al. 2002

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Menin, a nuclear protein encoded by the tumor suppressor gene MEN1, interacts with the AP-1 transcription factor JunD and inhibits its transcriptional activity. In addition, overexpression of Menin counteracts Ras-induced tumorigenesis. We show that Menin inhibits ERK-dependent phosphorylation and activation of both JunD and the Ets-domain transcription factor Elk-1. We also show that Menin represses the inducible activity of the c-fos promoter. Furthermore, Menin expression inhibits Jun N-terminal kinase (JNK)-mediated phosphorylation of both JunD and c-Jun. Kinase assays show that Menin overexpression does not interfere with activation of either ERK2 or JNK1, suggesting that Menin acts at a level downstream of MAPK activation. An N-terminal deletion mutant of Menin that cannot inhibit JunD phosphorylation by JNK, can still repress JunD phosphorylation by ERK2, suggesting that Menin interferes with ERK and JNK pathways through two distinct inhibitory mechanisms. Taken together, our data suggest that Menin uncouples ERK and JNK activation from phosphorylation of their nuclear targets Elk-1, JunD and c-Jun, hence inhibiting accumulation of active Fos/Jun heterodimers. This study provides new molecular insights into the tumor suppressor function of Menin and suggests a mechanism by which Menin may interfere with Ras-dependent cell transformation and oncogenesis.

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The tumor suppressor protein menin interacts with NF-κB proteins and inhibits NF-κB-mediated transactivation

Cited by 224 publications

References 37 publications

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

Menin represses JunD transcriptional activity in protein kinase Cθ-mediated Nur77 expression

Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation

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