PMC:4135037 / 2177-4018 JSONTXT

{"project":"2_test","denotations":[{"id":"24531709-15864278-79171849","span":{"begin":367,"end":368},"obj":"15864278"},{"id":"24531709-15864278-79171849","span":{"begin":367,"end":368},"obj":"15864278"},{"id":"24531709-19075677-79171850","span":{"begin":370,"end":371},"obj":"19075677"},{"id":"24531709-19075677-79171850","span":{"begin":370,"end":371},"obj":"19075677"},{"id":"24531709-15864278-79171851","span":{"begin":1263,"end":1264},"obj":"15864278"},{"id":"24531709-15864278-79171851","span":{"begin":1263,"end":1264},"obj":"15864278"},{"id":"24531709-11158604-79171852","span":{"begin":1504,"end":1505},"obj":"11158604"},{"id":"24531709-11158604-79171852","span":{"begin":1504,"end":1505},"obj":"11158604"},{"id":"24531709-12819299-79171852","span":{"begin":1504,"end":1505},"obj":"12819299"},{"id":"24531709-12819299-79171852","span":{"begin":1504,"end":1505},"obj":"12819299"},{"id":"24531709-19620250-79171852","span":{"begin":1504,"end":1505},"obj":"19620250"},{"id":"24531709-19620250-79171852","span":{"begin":1504,"end":1505},"obj":"19620250"}],"text":"Functional loss of a tumor suppressor gene is a key step of tumor initiation, triggering multi-step oncogenic events. A number of hereditary tumor syndromes result from germline mutations of tumor suppressor loci, providing implications about the mechanisms of tumor development. One of such examples is the cancer syndrome multiple endocrine neoplasia type 1 (MEN1) 1, 2. Individuals with germline mutations of the MEN1 gene are predisposed to develop hyperplasia and tumors in the endocrine pancreas, anterior pituitary and parathyroid. The MEN1 gene encodes a ubiquitously expressed transcriptional cofactor menin. Menin regulates gene transcription at least partly by modifying chromatin structure through its physical association with the mixed lineage leukemia (MLL) gene products MLL and MLL2, which are SET domain-containing histone lysine methyltransferases. The Menin-MLL complexes mediate tri-methylation of histone H3 at Lysine-4 (H3K4me3), a histone modification mark observed predominantly at transcriptionally active loci. Consistent with the role of menin as a bona fide tumor suppressor in neuroendocrine tissues, somatic MEN1 mutations are frequently found in sporadic pancreatic tumors and parathyroid tumors, and also in some pituitary tumors 1. While homozygous mice with targeted disruption of the Men1 gene are embryonic lethal, heterozygous mice are viable and develop tumors in the endocrine pancreas and parathyroid within 9 months of age, and pituitary tumors within 12 months 3-5. Tumors developed in Men1 +/− mice display loss of heterozygosity (LOH), which closely resembles MEN1 individuals. These data suggest that the functional loss of menin confers a selective advantage for pre-tumorigenic neuroendocrine cells, whereas the exact mechanism of such neuroendocrine-specific tumor initiation remains unclear."}