dimanche 5 février 2012

Mutated genes in cancer (49) – MEN1


In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 4221 or MEN1
● Ensembl (http://www.ensembl.org/index.html): ENSG00000133895
● UniProt (http://www.uniprot.org/): O00255
● GeneCards (http://www.genecards.org/): MEN1
● HGNC (http://www.genenames.org/): 7010 or MEN1

Gene locus:


Protein name:

Multiple endocrine neoplasia I

Protein Size:

615 amino acids; about 68 kDa


MEN1 product, menin, is a growth-suppressor gene. It interacts with the AP1 transcription factor through his JunD component, but with none of the other AP1 proteins, such as JunB, c-Jun, c-Fos and Fra1/2. Many cellular functions of menin have been identified. However, which ones of these relate specifically to menin's role as a tumor suppressor and which ones not remains unclear. Menin is predominantly nuclear and acts as a scaffold protein to regulate gene transcription by coordinating chromatin remodeling. It is implicated in both histone deacetylase and histone methyltransferase activity and, via the latter, regulates the expression of cell cycle kinase inhibitor and homeobox domain genes. TGF-beta family members are key cytostatic molecules and menin is a facilitator of the transcriptional activity of their signaling molecules, the Smads, thereby ensuring appropriate control of cell proliferation and differentiation (Hendy GN et al. 2009).

Cancer-related alterations:

Germline mutations in the MEN1 gene cause familial and sporadic multiple endocrine neoplasia type 1 (MEN1). Familial MEN1 is an autosomal dominant disorder characterized by a predisposition to endocrine tumors, including parathyroid, gastrointestinal endocrine tissue, endocrine pancreas, pituitary, adrenal glands, thymus… The majority of mutations described predict premature protein truncation either by nonsenses and frameshifts in coding sequences, but missense mutations have also been identified in about 30% of cases.
Between 10 and 15% of sporadic MEN1 could be explained by de novo mutations.
Approximately 10-15% of MEN1 families do not show any mutation in the known part of MEN1 sequence; clinical profile in these families do not differ from that of families with identified mutations and it is therefore possible that MEN1 mutations occur outside the coding sequence
Prognosis in MEN1 patients is mainly related to metabolic and organic complications of hormonal hypersecretion by tumoral cells, such as hypergastrinemia causing severe peptic ulcer disease (Zollinger-Ellison syndrome, ZES), primary hyperparathyroidism, and acute forms of hyperinsulinemia.

It seems that some MEN1 families could express only primary hyperparathyroidism, so called familial primary hyperparathyroidism (FIHPT), an allelic variant of MEN1. FIHPT is an autosomal dominant disorder characterized by hypercalcemia, elevated parathyroid hormone (PTH) levels, and uniglandular or multiglandular parathyroid tumors.

References (open access):

Cellular functions of menin. Hendy GN, Kaji H, Canaff L. Adv Exp Med Biol. 2009;668:37-50.

The menin tumor suppressor protein is phosphorylated in response to DNA damage. Francis J, Lin W, Rozenblatt-Rosen O, Meyerson M. PLoS One. 2011 Jan 14;6(1):e16119.

Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Harding B, Lemos MC, Reed AA, Walls GV, Jeyabalan J, Bowl MR, Tateossian H, Sullivan N, Hough T, Fraser WD, Ansorge O, Cheeseman MT, Thakker RV. Endocr Relat Cancer. 2009 Dec;16(4):1313-27.

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