In search of tumor suppressing functions of menin

Abstract

Human hereditary tumor syndromes serve as an ideal model for studying molecular pathways regulating tumorigenesis. Multiple endocrine neoplasia type 1 (MEN1), a human familial tumor syndrome, results from mutations in the Men1 gene. Men1 encodes a novel tumor suppressor, menin, of unknown biochemical function. Recently, significant progress has been made in identifying menin as a regulator of gene transcription, cell proliferation, apoptosis, and genome stability, leading to a new model of understanding menin's tumor-suppressing function. These findings suggest that menin's diverse functions depend on its association with chromatin and its control over gene transcription. This knowledge will likely be translated into new strategies to improve therapeutic interventions against MEN1 and other related cancers.

Figure 1

A schematic model explaining how menin regulates gene transcription. (a) Menin and a hypothetically specific DNA binding protein (TF₁), together with transcription-activating histone methyltransferases (HMTs), such as MLL or MLL2, target to the loci of p18^ink4c, p27^kip1 and Hoxc8 genes in chromatin. This HMT-containing complex methylates lysine 4 on histone H3, and changes chromatin structure and subsequently activates gene transcription. Activation of p18^ink4c, p27^kip1 and Hoxc8 genes leads to cell growth inhibition or cell differentiation. (b) Menin and a hypothetically specific DNA binding protein (TF₂), together with a histone deacetylase (HDAC), may target the loci of menin target genes such as hTERT and IGFBP-2, to remove the acetyl group on histones and thus repress the target gene transcription. Inhibition of hTERT and IGFBP-2 may result in reduced cell proliferation and maintenance of genomic stability. Interaction of menin and HDACs in regulating endogenous genes remains to be determined.

Figure 2

A schematic model showing how menin regulates cell proliferation via distinct mechanisms. Menin represses expression of Cyclin D1 and D3, which form an active kinase with cyclin-dependent kinase (CDK4), promoting cell cycle progression from G1 to S phase. Menin also upregulates the expression of p18^ink4c and p27^kip1, and represses cyclin-dependent kinase 2 (CDK2) activity and G0/1 to S transition. Cdc7/ activator of S-phase kinase (ASK) complex possesses protein kinase activity phosphorylating mini-chromosome maintenance (MCM) protein, and is essential for DNA replication and S phase progression. Menin interacts with ASK and inhibits ASK-induced cell proliferation. It is likely that, through either transcriptional or post-transcriptional regulation, menin represses CDK4/Cyclin D, CDK2/Cyclin A or E, and Cdc7/ASK, leading to repression of cell cycle transition from G1 to S phase or progression through the S phase.

Figure 3

A model for regulation of genome stability by menin via association with various nuclear proteins. Menin associates with chromatin and, upon DNA damage induced by ionizing irradiation or DNA crosslinking, increases its affinity with FancD2, a protein involved in DNA repair and genome stability. In addition, menin also interacts with Cdc7/ASK (activator of S-phase kinase), which is also involved in DNA replication and repair, and with monomeric RPA2 (replication protein A2). DNA damage may increase menin's affinity with these interacting proteins and thus form a supper complex on the chromatin. Although menin alone interacts with each of the above proteins, it remains to be shown whether it forms a supper complex with the other four proteins simultaneously. Menin also represses hTERT (human telomere reverse transcriptase) and thus may protect genome stability indirectly. Because menin's prominent role in regulating gene transcription, it is also possible some of its target genes are involved in maintaining genome stability (Scacheri et al., 2006).