Positional Cloning of the Gene for Multiple Endocrine Neoplasia-Type 1

Chandrasekharappa, Settara C.; Guru, Siradanahalli C.; Manickam, Pachiappan; Olufemi, Shodimu Emmanuel; Collins, Francis S.; Emmert‐Buck, Michael R.; Debelenko, Larisa V.; Zhuang, Zhengping; Lubensky, Irina A.; Liotta, Lance A.; Crabtree, Judy S.; Wang, Ying‐Ping; Roe, Bruce A.; Weisemann, Jane M.; Boguski, Mark S.; Agarwal, Sunita K.; Kester, Mary Beth; Kim, Young S.; Heppner, Christina; Dong, Qihan; Spiegel, Allen M.; Burns, A. Lee; Marx, Stephen J.

doi:10.1126/science.276.5311.404

Cited by 1,821 publications

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References 21 publications

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“…However, the individual genes are not closely located to each other in the mouse genome, where fra-1 is on chromosome 19, c-fos on chromosome 12, and fosB on chromosome 7 (D 'Eustachio, 1984;Lazo et al, 1991). The human fra-1 gene has been localised by`reverse mapping' to chromosome 11q13, a region which was found to be ampli®ed in a number of neoplastic disorders and contains the MEN1 gene, a putative tumor suppressor gene (Sinke et al, 1993;Tanigami et al, 1992;Brookes et al, 1992;Chandrasekharappa et al, 1997; The European Consortium on MEN1, 1997). We have mapped the mouse fra-1 gene to the pericentromeric region of chromosome 19, which is syntenic to that region of human chromosome 11.…”

Section: Discussionmentioning

confidence: 99%

Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis)

et al. 1997

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We have determined the genomic structure of the mouse fra-1 gene, which consists of four exons and three introns at positions also found in the other members of the fos gene family. Fra-1 is expressed rather highly in the brain and testes of adult mice, and at low levels in most other tissues. Absence of c-Fos leads to signi®cantly reduced serum stimulation of fra-1 expression in gene targeted mouse ®broblasts, demonstrating that mitogen induction of fra-1 is partially mediated by c-Fos/AP-1. A polymorphic (CA) n microsatellite marker was found in intron 2 of fra-1 and used to map the gene to the centromeric region of mouse chromosome 19. Since fra-1 maps to the same genomic region as oc (osteosclerosis), an autosomal recessive disorder leading to the bone remodelling disease osteopetrosis, we tested it as a candidate gene for oc. The segregation of fra-1 in two di erent crosses of mice carrying oc and an allelism test between oc and a targeted disruption of fra-1 demonstrate that fra-1 and oc are two distinct genes rather than oc being a mutant allele of fra-1.

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Section: Discussionmentioning

confidence: 99%

Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis)

et al. 1997

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“…The last component of this MLL complex is menin, also found to interact with MLL2 [Hughes et al, 2004]. Menin is a tumor suppressor and mutations in this gene have been implicated in multiple endocrine tumors [Chandrasekharappa et al, 1997]. Similar to the AT-hooks of MLL, menin can bind to various DNA structures in a sequence-independent manner [La et al, 2004].…”

Section: The Story Is Two Complexmentioning

confidence: 99%

MLL: How complex does it get?

Popovic

Zeleznik‐Le

2005

J of Cellular Biochemistry

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The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain-and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered. J. Cell. Biochem. 95: 234-242, 2005. ß 2005 Wiley-Liss, Inc.

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“…4 MEN1 results from germline mutations of MEN1, a 10-exon gene located on chromosome 11q13 that encodes for menin, a 610-amino-acid protein. 3,[5][6][7][8] Recent studies suggest menin regulates the transcription of multiple differentiation-regulating genes in association with a histone methyltransferase complex. 9 Mutations of the MEN1 gene and allelic loss of chromosome 11q13 are reported in sporadic carcinoid tumors and sporadic pancreatic endocrine tumors.…”

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Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

et al. 2005

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Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations. We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P ¼ 0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P ¼ 0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P ¼ 0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P ¼ 0.02). Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.

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Positional Cloning of the Gene for Multiple Endocrine Neoplasia-Type 1

Cited by 1,821 publications

References 21 publications

Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis)

Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis)

MLL: How complex does it get?

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

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