Multiple endocrine neoplasia type 1 pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
Overview
Pathogenesis
- Pathogenesis is the mechanism by which a certain factor causes disease (pathos = disease, genesis = development). The term can also be used to describe the development of the disease, whether it is acute, chronic, or recurrent. It can also be used to describe whether the disease causes inflammation, malignancy,necrosis etc.
- For an example of a pathogenesis section within a pathophysiology page, click here
Genetics
MEN1 gene
- The gene locus causing MEN1 has been localised to chromosome 11q13 by studies of loss of heterozigosity (LOH) on MEN1-associated tumours and by linkage analysis in MEN1 families [27-30].
- The results of these studies agree with Knudson's "two hits" model for tumour development[31] and indicated that the MEN1 gene is a putative tumour suppressor gene.
- The mutated MEN1allele is a germline mutation present in all cells at birth. The second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele; it gives cells the survival advantage needed for tumour development.
- The responsible gene, MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
- Mutation analysis revealed that the MEN1 gene was frequently, but not always, mutated in MEN1 families[32]. To date, more than 400 different germline or somatic mutations have been reported in MEN1 families and sporadic cases from several international studies.
- Mutations are distributed over the entire coding region without showing any significant hot spot region [33-38].
- 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.
- The nonsense mutations and many of the frameshift insertions and deletions and donor-splice site mutations are truncating mutations predicting a loss-of-function of menin, and therefore supporting the hypothesis that MEN1 is a tumour suppressor gene.
- About 68% of identified missense mutations occur on an amino acid that is conserved among humans, mice, zebrafish and Drosophila.
- More than 10% of the MEN1mutations arise de novo and may be transmitted to subsequent generations. Nevertheless, about 10–20% of MEN1 patients may not harbour mutations within the coding region of the MEN1 gene[15,33-35,39]; these individuals may have mutations in the promoter or untranslated regions (UTRs), which remain to be investigated. Moreover, because all MEN1 families investigated to date have tight linkage to 11q13, the presence of another tumour suppressor gene in this region is also a possibility [40].
MEN1 protein (menin)
- MEN1 gene encodes a 610 amino acid (67 Kda) nuclear protein that is highly conserved among humans, mice (98%) and rats (97%), and more distantly among zebrafish (75%) and Drosophila(47%) [41-45]. Analysis of the menin amino acid sequence did not reveal homology to any other known protein, sequence motif or signal peptide, thus the putative function of menin could not be deduced. Since the amino acid sequence and mutation profile of menin provide a few clues to the functions of menin, most of what is known about its role is derived from in vitro studies. These studies revealed that menin is located primarily in the nucleus [46] and identified at least two independent nuclear localisation signals (NLSs) in the C-terminus of the protein. None of the MEN1missense mutations or in-frame deletions [3,15,33-36,47-50] alter either of these NLSs. However, all truncating mutations induce a lack of at least one of these NLSs. The nuclear localisation of menin suggests that this protein may have an important role in the regulation of DNA transcription and replication, in cell cycle, or in the maintenance of genome integrity. Recent studies have demonstrated that over-expression of menin in a Ras-transformed NIH3T3 cell model reversed the transformed phenotype [51], inducing decreased proliferation, suppression of growth in soft agar and inhibition of tumour growth in nude mice. There is increasing evidence that menin may act in DNA repair or synthesis, but the exact mechanism by which menin regulates DNA synthesis or DNA repair in response to DNA damage, is currently unknown. In the last years menin has been shown to interact with several proteins of known functions.
- 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 (which are critical for this interaction). Wild type menin represses JunD-activated transcription maybe via a histone deacetylase-dependent mechanism [52,53].
- 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) [54]. 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 (TGFβ) signalling pathway at the level of Smad3. Alteration of the TGFβ signalling pathways is important in pancreatic carcinogenesis.
- Even the rodent protein Pem has been shown to bind menin directly [55]. Pem is a homeobox-containing protein which plays a role in the regulation of transcription. However, since Pem sequence has no known homolog in the human genome, its direct relevance to MEN1 in humans is still controversial. Mouse and human menin are very similar and this could suggest the existence of a human protein, with a function similar to that of Pem, which binds menin and thus plays a role in the pathogenicity of MEN1 mutations.
- 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 [56]. 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. This may be supported by the fact that normal cells from MEN1 patients present an elevated level of chromosome alterations [57-60] and that MEN1 tumours have more genome aberrations than equivalent tumours from non-MEN1 patients [61].