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Insulinomas (pancreatic islet β cell tumors) are the most common type of functioning pancreatic neuroendocrine tumors that occur sporadically or as a part of the MEN1 syndrome that is caused by germ line mutations in MEN1. Tissue-specific tumor predisposition from germ line mutations in ubiquitously expressed genes such as MEN1 could occur because of functional consequences on tissue-specific factors. We previously reported the proapoptotic β cell differentiation factor HLXB9 as a downstream target of menin (encoded by MEN1). Here we show that GSK-3β inactivates the proapoptotic activity of HLXB9 by phosphorylating HLXB9 at Ser-78/Ser-80 (pHLXB9). Although HLXB9 is found in the nucleus and cytoplasm, pHLXB9 is predominantly nuclear. Both pHLXB9 and active GSK-3β are elevated in β cells with menin knockdown, in MEN1-associated β cell tumors (insulinomas), and also in human sporadic insulinomas. Pharmacologic inhibition of GSK-3β blocked cell proliferation in three different rodent insulinoma cell lines by arresting the cells in G2/M phase and caused apoptosis. Taken together, these data suggest that the combination of GSK-3β and pHLXB9 forms a therapeutically targetable mechanism of insulinoma pathogenesis. Our results reveal that GSK-3β and pHLXB9 can serve as novel targets for insulinoma treatment and have implications for understanding the pathways associated with β cell proliferation.

Operation for multiple endocrine neoplasia (MEN)1-related hyperparathyroidism (HPT) includes a neck exploration with resection of 3.5 or 4 parathyroid glands and transcervical thymectomy (TCT). We reviewed our experience with initial operation for primary HPT to determine the outcome and utility of routine TCT.All patients with MEN1 who underwent initial neck exploration from 1993 to 2007 under an institutional review board-approved protocol were reviewed.We identified 66 patients with initial operation for HPT in MEN1. In 34 patients, 4 glands were found; in 32 patients,4 glands were found. In 2 of the 34 (6%) and 17 of the 32 (53%), intrathymic parathyroid tissue was found on permanent pathology. No thymic carcinoid tissue was found in any specimen.These data highlight the importance of performing TCT when4 entopic parathyroid glands are found at first operation.

Multiple endocrine neoplasia type 1 (MEN1) provides a prime example of how a rare disease can advance our understanding of basic cell biology, neoplasia and common endocrine tumors. MEN1 is expressed mainly as parathyroid, enteropancreatic neuroendocrine, anterior pituitary and foregut carcinoid tumors. It is an autosomal dominant disease caused by mutation of the MEN1 gene. Since its identification, the MEN1 gene has been implicated in many common endocrine and non-endocrine tumors. This is a brief overview of recent scientific advances relating to MEN1, including newly recognized clinical features that are now better characterized by genetic analysis, insights into the function of the MEN1-encoded protein menin, and refined recommendations for mutation testing and tumor screening, which highlight our increasing understanding of this complex syndrome.

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by tumors of the parathyroid, entero-pancreatic neuroendocrine and pituitary tissues and caused by inactivating mutations in the MEN1 gene. Menin, the 610-amino acid nuclear protein encoded by MEN1 , binds to the transcription factor JunD and can repress JunD-induced transcription. We report here the identification of a MEN1 ortholog in Drosophila melanogaster , Menin1 , that encodes a 763 amino acid protein sharing 46% identity with human menin. Additionally, 69% of the missense mutations and in-frame deletions reported in MEN1 patients appear in amino acid residues that are identical in the Drosophila and human protein, suggesting the importance of the conserved regions. Drosophila Menin1 gene transcripts use alternative polyadenylation sites resulting in 4.3 and 5-kb messages. The 4.3-kb transcript appears to be largely maternal, while the 5-kb transcript appears mainly zygotic. The binding of Drosophila menin to human JunD or Drosophila Jun could not be demonstrated by the yeast two-hybrid analysis. The identification of the MEN1 ortholog from Drosophila melanogaster will provide an opportunity to utilize Drosophila genetics to enhance our understanding of the function of human menin.

MEN1 is a tumor suppressor gene that encodes a 610 amino acid nuclear protein (menin) of previously unknown function. Using a yeast two-hybrid screen with menin as the bait, we have identified the transcription factor JunD as a direct menin-interacting partner. Menin did not interact directly with other Jun and Fos family members. The menin–JunD interaction was confirmed in vitro and in vivo. Menin repressed transcriptional activation mediated by JunD fused to the Gal4 DNA-binding domain from a Gal4 responsive reporter, or by JunD from an AP1-responsive reporter. Several naturally occurring and clustered MEN1 missense mutations disrupted menin interaction with JunD. These observations suggest that menin's tumor suppressor function involves direct binding to JunD and inhibition of JunD activated transcription.

Primary hyperparathyroidism is characterized by hypercalcemia and elevated parathyroid hormone levels. It can be caused by overactivity of one (adenoma or carcinoma) or more (hyperplasia or multiple adenoma) parathyroid glands. Parathyroid adenoma and hyperplasia are usually mono- or oligoclonal neoplasms. To establish whether parathyroid cancer has a genetic composition distinct from parathyroid adenoma, we analyzed 10 adenoma and 10 carcinoma cases by comparative genomic hybridization (CGH). Results show clear differences between the constitution of adenoma and carcinoma genomic DNA. The most frequent genomic alterations in adenoma included deletions on chromosomes 11, 17 (5 of 10 cases), and 22 (7 of 10 cases). In parathyroid carcinoma, frequent chromosomal deletions were on chromosome arm 1p (4 of 10 cases) and chromosome 17 (3 of 10 cases), and gains were on chromosome 5 (3 of 10 cases). Our data indicate that different genetic changes could contribute to the development of parathyroid adenoma and carcinoma; genomic losses predominate in adenoma, and gains along with some losses are found in carcinoma. Furthermore, the CGH results implicate several chromosomal regions that may harbor genes that could be potentially involved in the development of parathyroid adenoma and carcinoma. Published by Elsevier Science Inc.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder that results in parathyroid, anterior pituitary, and pancreatic and duodenal endocrine tumors in affected individuals. The MEN1 locus is tightly linked to the marker PYGM on chromosome 11q13, and linkage analysis has placed the MEN1 gene within a 2-Mb interval flanked by D11S1883 and D11S449. As a step toward cloning the MEN1 gene, we have constructed a 2.8-Mb clone contig consisting of YAC and bacterial clones (PAC, BAC, and P1) for the D11S480 to D11S913 region. The bacterial clones alone represent nearly all of the 2.8-Mb contig. The contig was assembled based on a high-density STS-content analysis of 79 genomic clones (YAC, PAC, BAC, and P1) with 118 STSs. The STSs included 22 polymorphic markers and 20 transcripts, with the remainder primarily derived from the end sequences of the genomic clones. An independent cosmid contig for the 1-Mb PYGM-SEA region was also generated. Support for correctness of the 2.8-Mb contig map comes from an independent ordering of the clones by fiber-FISH. This sequence-ready contig will be a useful resource for positional cloning of MEN1 and other disease genes whose loci fall within this region.

The apt gene, coding for adenine phosphoribosyltransferase (APRT), has been isolated from the plant Arabidopsis thaliana. Data from both Southern analysis and characterization of apt clones isolated from a genomic library is consistent with the occurrence of one apt within the A. thaliana genome. Comparison of the nucleotide sequence of the apt gene with its corresponding cDNA indicates that the gene contains five introns, whereas all other apt isolated to date have fewer introns (four in mammals, two in Drosophila). The locations of the introns within the plant apt coding region are not consistent with the placement of introns in the previously isolated apt of murines, human and Drosophila species. In agreement with its expression pattern in vivo, the upstream region of this plant apt is able to express the β-glucuronidase-encoding gene (gus) in an apparently constitutive manner in transgenic A. thaliana plants. The apt promoter region is notable for its lack of conventional promoter elements such as TATA, CCAAT or G + C-rich sequence elements.