Menin represses tumorigenesis via repressing cell proliferation

Abstract

Multiple endocrine neoplasia type 1 (MEN1) results from mutations in the tumor suppressor gene, MEN1, which encodes nuclear protein menin. Menin is important for suppressing tumorigenesis in various endocrine and certain non-endocrine tissues. Although menin suppresses MEN1 through a variety of mechanisms including regulating apoptosis and DNA repair, the role of menin in regulating cell proliferation is one of the best-studied functions. Here, we focus on reviewing various mechanisms underlying menin-mediated inhibition of cell proliferation. Menin inhibits cell proliferation to repress MEN1 through multiple mechanisms. 1) Menin interacts with various histonemodifying enzymes, such as MLL, EZH2 and HDACs, to affect gene transcription, leading to repression of cell proliferation. 2) Menin also interacts with various transcription factors, such as JunD, NF-κB, PPARγ and VDR, to induce or suppress gene transcription. As these various transcription factors are known to regulate cell proliferation, their interaction with menin may be relevant to menin's role in inhibiting cell proliferation. 3) Menin inhibits cell proliferation via TGF-β signaling and Wnt/β-catenin signaling pathways. 4) Menin represses certain pro-proliferative factors involved in endocrine tumors such as IGFBP-2, IGF2 and PTHrP to repress cell proliferation. 5) Menin affects cell cycle progression to inhibit cell proliferation. This review is helpful in our understanding of the comprehensive mechanisms whereby menin represses MEN1 through inhibiting cell proliferation.

Keywords: Menin; cell cycle; cell proliferation; epigenetics; gene transcription.

Figure 1

Menin inhibits cell proliferation via various mechanisms. A, Menin interacts with MLL and recruits MLL to the promoter of CDKN1B and CDKN2C (encoding p27^Kip1 and p18^Ink4c proteins) and enhances H3K4me3 level. Expression of p27^Kip1 and p18^Ink4c is activated, and the cell cycle G1/S transition is arrested. B, Menin interacts with MLL and represses the expression of Hox genes to inhibit cell proliferation. C, Menin recruits EZH2 to the promoter of PTN and represses PTN transcription through increasing H3K27me3 level, thus inhibiting cell proliferation. D, Menin recruits HDACs to the promoter of cyclin B2 and represses cyclin B2 transcription via decreasing histone H3 acetylation level, leading to arrest at G2/M transition. E, Menin associates with HDACs and interacts with the transcription factor, JunD, to represses JunD-activated transcription leading to inhibition of cell proliferation. F, Menin interacts with NF-κB and represses NF-κB-mediated Cyclin D1 transcription and inhibition of cell proliferation. G, Menin interacts with the nuclear receptor PPARγ to repress cell proliferation. H, Menin interacts with the nuclear receptor VDR to repress cell proliferation. I, Menin interacts with Smad3 and enhance the TGF-β signaling pathway to inhibit cell proliferation. J, Menin interacts with β-catenin and affects the Wnt/β-catenin signaling pathway to repress cell proliferation. K, Menin represses IGFBP-2, IGF2, and PTHrP proliferative factors involved in endocrine tumors to repress cell proliferation. L, Menin interacts with the activator of S-phase kinase (ASK) and represses ASK -induced cell proliferation. The question mark represents the related mechanism needs to be further investigated.