Multiple Endocrine Neoplasia Type I

Sj, Marx; Ai, Vinik; Rj, Santen; Jc, Floyd; Mills, James L.; Green, J

doi:10.1097/00005792-198607000-00003

Cited by 99 publications

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“…One of the most common features of MEN1 patients is primary hyperparathyroidism, which occurs in over 95% of MEN1 patients over age 40 as a result of parathyroid adenoma or hyperplasia (1,(23)(24)(25)(26)(27). Consistent with this human phenotype, Men1 TSM/ϩ mice develop focal dysplasia throughout the course of the time study, with 6͞25 (24%; 4͞14 male, 2͞11 female) animals developing parathyroid adenoma as early as 9 months of age (Fig.…”

Section: Men1 Gene Targetingmentioning

confidence: 73%

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors

Crabtree

Scacheri

Ward

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene.M ultiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome characterized by multiple tumors of the parathyroid, endocrine pancreas, and the anterior pituitary. Additional tumors have been associated with MEN1, including foregut carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma (1, 2). Linkage studies in affected families mapped the MEN1 locus to chromosome 11q13 (3), and the responsible gene, MEN1, was identified by positional cloning in 1997 (4). Germline mutations in MEN1 have been identified in almost all MEN1 kindreds (5-7), and somatic mutations in MEN1 have been reported in sporadic parathyroid adenomas, pituitary tumors, insulinomas, gastrinomas, and lung carcinoids (8 -12). Over 70% of germline mutations are nonsense and frameshifts, predicting truncation or absence of the resulting protein.Missense mutations and in-frame deletions account for the remaining 30% of the almost 250 unique mutations identified to date. Hence, MEN1 appears to be a classic tumor suppressor gene with tumors in affected patients showing somatic loss of the wild-type allele.The MEN1 gene consists of 10 exons (the first of which is untranslated), spanning 7.2 kb of genomic sequence and encoding a protein of 610 amino acids. The protein product, menin, does not reveal homologies to any other known proteins or possess notable motifs from which the putative function of the protein could be deduced. Menin RNA and protein apparently are expressed in all tissues (13), leaving unexplained the basis for endocrine predominance of neoplasia. Menin is found in the nucleus (14) and binds to the AP1 transcription factor JunD (15). This finding suggests a role in transcriptional regulation, although a detailed model for menin tumor suppression ...

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Section: Men1 Gene Targetingmentioning

confidence: 73%

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors

Crabtree

Scacheri

Ward

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

415

352

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“…The above studies in cultured cells showed a crucial role for menin in controlling S-phase entry. However, it is still unclear whether this role of menin also applies to in vivo endocrine cells such as pancreatic islet cells, in which a germ-line mutation in only one Men1 allele predisposes the patient to the development of insulinomas (28). In addition, because it takes f6 months for mice carrying a Men1 mutation to develop insulinomas, which have a high proliferation index (17), an important unresolved question is whether time-controlled Men1 excision can quickly lead to enhanced proliferation of pancreatic islet cells.…”

Section: Ink4cmentioning

confidence: 99%

Mutation of Tumor Suppressor Gene Men1 Acutely Enhances Proliferation of Pancreatic Islet Cells

et al. 2006

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Multiple endocrine neoplasia type 1 (MEN1), an inherited tumor syndrome affecting endocrine organs including pancreatic islets, results from mutation of the tumor suppressor gene Men1 that encodes protein menin. Although menin is known to be involved in regulating cell proliferation in vitro, it is not clear how menin regulates cell cycle and whether mutation of Men1 acutely promotes pancreatic islet cell proliferation in vivo. Here we show that excision of the floxed Men1 in mouse embryonic fibroblasts (MEF) accelerates G 0 /G 1 to S phase entry. This accelerated S-phase entry is accompanied by increased cyclin-dependent kinase 2 (CDK2) activity as well as decreased expression of CDK inhibitors p18Ink4c and p27Kip1 . Moreover, Men1 excision results in decreased expression of p18 Ink4c and p27 Kip1 in the pancreas. Furthermore, complementation of menin-null cells with wild-type menin represses S-phase entry. To extend the role of menin in repressing cell cycle in cultured cells to in vivo pancreatic islets, we generated a system in which floxed Men1 alleles can be excised in a temporally controllable manner. As early as 7 days following Men1 excision, pancreatic islet cells display increased proliferation, leading to detectable enlargement of pancreatic islets 14 days after Men1 excision. These observations are consistent with the notion that an acute effect of Men1 mutation is accelerated S-phase entry and enhanced cell proliferation in pancreatic islets. Together, these results suggest a molecular mechanism whereby menin suppresses MEN1 tumorigenesis at least partly through repression of G 0 /G 1 to S transition. (Cancer Res 2006; 66(11): 5707-15)

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“…It has been suggested that the duodenum rather than the pancreas is the major site of gastrinomas in MEN- 1.13 Twenty-two (20%) of the 110 living patients classified as highly or very highly probable had peptic ulcer symptoms associated with elevated calcium and gastrin levels and some of these had symptomatic pituitary lesions also, so that they may be considered to have manifested the dis¬ order at three separate sites. (5) Zollinger-Ellison syndrome; (6) 6,7,9,10,12 50% /2/…”

Section: Subjectsmentioning

confidence: 99%

“…Parent of patients 6, 7, 9, 10, 12 50% 2/3/F 1861-1861 Sibling of patients 6,7,9,10,12 Sibling of patients 6, 7, 9, 10, 11 50% 2/138/M 1848-? Sibling of patients 6,7,9,10, 1895-1969 1912 1936 1987 1913-1981 1914-1949 1939 1966 1915-1986 1923-1967 1926 1968 1950 1952 NT; father of patient 638 NT; mother of patient 666 1989, NAD; child of patient 638 1984, 1987, 1988, …”

Section: -1895mentioning

confidence: 99%

The Natural History of Multiple Endocrine Neoplasia Type 1

1991

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Among 2000 descendants of an English immigrant to Tasmania, Australia, the diagnosis of multiple endocrine neoplasia type 1 was found to be very highly probable or highly probable in 130 and moderately probable in 22. Another 242 children and siblings were 50% likely to have inherited this dominant gene. In all age groups, especially the elderly, the majority of affected members had symptoms of only one endocrine disorder or were asymptomatic. In teenagers, the most common presentation was pituitary lesions and the second most common presentation was insulinomas. Frequently, pituitary lesions or insulinomas developed before any parathyroid lesions could be detected. Elevation of gastrin levels, usually associated with hypercalcemia, was rarely seen in patients younger than 25 years. The classic presentation with symptoms of multiple endocrinopathy may represent only a small fraction of these patients in the community.

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Multiple Endocrine Neoplasia Type I

Cited by 99 publications

References 0 publications

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors

Mutation of Tumor Suppressor Gene Men1 Acutely Enhances Proliferation of Pancreatic Islet Cells

The Natural History of Multiple Endocrine Neoplasia Type 1

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