Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1

Abstract

Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant cancer predisposition syndrome, the gene for which encodes a nuclear protein, menin. The biochemical function of this protein has not been completely elucidated, but several studies have shown a role in transcriptional modulation through recruitment of histone deacetylase. The mechanism by which MEN1 mutations cause tumorigenesis is unknown. The Drosophila homolog of MEN1, Mnn1, encodes a protein 50% identical to human menin. In order to further elucidate the function of MEN1, we generated a null allele of this gene in Drosophila and showed that homozygous inactivation results in morphologically normal flies that are hypersensitive to ionizing radiation and two DNA cross-linking agents, nitrogen mustard and cisplatinum. The spectrum of agents to which mutant flies are sensitive and analysis of the molecular mechanisms of this sensitivity suggest a defect in nucleotide excision repair. Drosophila Mnn1 mutants have an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats, a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. Our data indicate that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA and HNPCC genes.

Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression

“…Recent progress in studying the function of menin suggests that menin has diverse functions, including regulation of gene transcription (Agarwal et al, 1999;Kaji et al, 2001;Lin and Elledge, 2003;Hughes et al, 2004;La et al, 2004a;Schnepp et al, 2004b), cell proliferation (Kim et al, 1999;Kaji et al, 2001;La et al, 2004b;Ratineau et al, 2004;Schnepp et al, 2004a), apoptosis (Sayo et al, 2002;Schnepp et al, 2004b) and genome stability (Scappaticci et al, 1992;Jin et al, 2003;Busygina et al, 2004). Menin is primarily a nuclear protein and possesses two classic nuclear localization signals, NLS1 and NLS2 (Guru et al, 1998).…”

The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression

“…Although the primary sequence of menin is highly conserved from fly to human, it does not bear obvious homology to known protein motifs, making it difficult to elucidate its biochemical function. Recent progress showed that menin regulates cell proliferation (5-7), apoptosis (8,9), and genome stability (10)(11)(12). Many of these functions rely on the ability of menin to regulate transcription of various genes, including cyclin-dependent kinase inhibitors and caspase 8 (9,13).…”

Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory

“…9 -13 However, several investigations suggest that MEN1 may be involved in the maintenance of genomic integrity in a manner similar to that of BRCA1 and BRCA2 or the genes underlying HNPCC, which also show LOH in tumors. 14,15 The discovery of the MEN1 gene by positional cloning in 1997 resulted in the development of genetic tests for responsible mutations. 16,17 Dispersed nonsense, missense, frameshift, in-frame deletions, and splice-site mutations have been described in the syndrome, with the majority of pedigrees having unique mutations.…”