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

Abstract

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.

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

“…The mechanism by which Menin represses JunD is still unclear. Recently, it was suggested that Menin inhibits JunD transcriptional activity by uncoupling of MAP kinase activation from MAP kinase-mediated phosphorylation of JunD (Gallo et al, 2002). Recently, we provided direct evidence that Menin recruits HDACs through association with mSin3A, a general transcriptional corepressor (Kim et al, 2003).…”

Multiple facets of junD gene expression are atypical among AP-1 family members

“…The recruitment of p300 derepresses JunD activity, presumably by reversing HDAC-mediated silencing of the Nur77 promoter (Kim et al, 2005). Repression of MEN1 also allows ERK2-mediated JunD phosphorylation, thus providing a pleiotropic effect (Gallo et al, 2002). The phosphorylation of JunD is dependent on repression of MEN1, but not on recruitment of p300.…”

“…Both of N-and C-terminal regions of MEN1 are needed for efficient JunD binding (Gobl et al, 1999). MEN1 negatively effects ERK-and JNK-dependent phosphorylation of JunD, without affecting the activation of either kinase (Gallo et al, 2002). The observation that a deletion mutant of MEN1 interferes with ERK2-dependent phosphorylation of JunD, but does not suppress phosphorylation by JNK, indicates that MEN1 affects each of these pathways by a distinct mechanism (Gallo et al, 2002).…”

“…The evidence is that MEK1-ERK1/2 specific inhibitors PD98059 and UO126 reduce the phosphorylated form of JunD, and that constitutively active forms of the ERK2 enhance JunD phosphorylation (presumably at the same positions as JNK) (Gallo et al, 2002). Figure 2 summarizes the outcome of Ras signaling of ERK2 and JNK/ERK2 on JunD.…”

JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress

“…Since this antibody detects phospho-JunD Ser100 protein due to conserved amino-acid sequences in this region between cJun and JunD, we concluded that phosphorylation of at least Ser100 of JunD was induced by H 2 O 2 or t-BHQ treatment. JunD was shown to be activated through phosphorylation of these serines and threonine by activated ERK1/2 (Gallo et al, 2002) or JNK (Yazgan and Pfarr, 2002). We observed that H 2 O 2 but not t-BHQ activates JNK, and both H 2 O 2 and t-BHQ activate ERK1/2 in several cell lines including HepG2 (Y Tsuji, unpublished data), suggesting that H 2 O 2 may utilize JNK and ERK1/2, and t-BHQ may utilize ERK1/2 for JunD phosphorylation.…”