Endocrine Abstracts

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor predisposition syndrome characterized by pituitary, parathyroid and enteropancreatic endocrine tumors. Molecular genetic studies of patients with MEN1 indicate that the MEN1 gene functions as a tumor suppressor gene with germline loss-of-function mutations in one allele, and somatic loss-of-function mutations of the second allele causing tumor formation. The gene is highly conserved in all vertebrate species including zebrafish, and an ortholog occurs in fruit fly but not yeast or roundworm. Menin, the product of the MEN1 gene, is a 610 amino acid protein in humans with no known homology to other proteins. The only known functional motifs are a pair of nuclear localization sequences near the carboxy-terminus, and these have been shown to lead to nuclear localization.
Homozygous disruption of the gene in mice is embryonic lethal, while germline heterozygous gene knockout leads to endocrine tumors closely mimicking the human phenotype. Tissue-specific MEN1 knockouts have been generated in parathyroids and islet beta cells, and these show tumor formation and biochemical evidence of excess hormone secretion.
Biochemical studies have shown that menin can interact with a number of proteins, including transcription factors junD, NF-kappaB, and smad3, but the physiologic significance of these interactions remains unclear. In an effort to define menin's function, we have studied the fruit fly menin ortholog (Dmenin). Overexpression of Dmenin, depending on the promoter used to drive expression, can lead to pupal lethality or defects in thoracic closure. The latter is significant in that the jun homolog in flies is known to be involved in thoracic closure. Identification of suppressor genes that rescue the phenotype caused by menin overexpression, and studies of the consequences of disruption of the fly gene, should help clarify the normal function of Dmenin, and may offer insight into its function in humans.