Sandbox MEN genetics
- The gene locus causing MEN1 has been localised to chromosome 11q13 by studies of loss of heterozigosity (LOH) on MEN1-associated tumors and by linkage analysis in MEN1 families
- MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
- MEN1 gene is a putative tumor suppressor gene and causes type 1 multiple endocrine neoplasia by  Knudson's "two hits" model for tumor development.
- Knudson's "two hits" model for tumor development suggest that there is a germline mutation present in all cells at birth and the second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele. This "two hits" model gives cells the survival advantage needed for tumor development.
- Mutations are distributed over the entire coding region without showing any significant hot spot region
- Approximately 20% of mutations are nonsense mutations, about 50% are frameshift insertions and deletions, 20% are missense mutations and about 7% are splice site defects.

# Menin
- MEN1 gene encodes a 610 amino acid (67 Kda) nuclear protein called menin.
- The first identified partner of menin was JunD, a transcriptional factor belonging to the AP1 transcription complex family. Menin interacts with the N-terminus of JunD through its N-terminus and central domains. Wild type menin represses JunD-activated transcription maybe via a histone deacetylase-dependent mechanism..
- Menin interacts, directly, with three members of the nuclear factor NF-kB family of transcription regulators: NF-kB1 (p50), NF-kB2 (p52) and RelA (p65). These proteins modulate the expression of various genes and are involved in the oncogenesis of numerous organs. Menin interacts with NF-kB by its central domain and represses NF-kB-mediated transcription.
- Moreover, menin interferes with the transforming growth factor beta (TGF) signalling pathway at the level of Smad3. Alteration of the TGF signalling pathways is important in pancreatic carcinogenesis.
- Although menin has been identified primarily as a nuclear protein, recent studies have reported its interaction with the glial fibrillary acid protein (GFAP) and with vimentin (components of intermediate filaments (IFs)), suggesting a putative role in glial cell oncogenesis.
- Finally, menin interacts with the metastasis suppressor Nm23H1. This interaction enables menin to act as an atypical GTPase and to hydrolyze GTP. The binding of menin to Nm23H1 may be relevant also to the control of genomic stability, as Nm23H1 is associated to the centrosome that is involved in the maintenance of chromosome integrity.
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