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词条 MEN1
释义

  1. History

  2. Genomics

  3. Clinical implications

  4. Role in cancer

  5. Interactions

  6. References

  7. Further reading

  8. External links

{{for|a description of the cancer syndrome|MEN 1}}{{Infobox_gene}}Menin is a protein that in humans is encoded by the MEN1 gene.[1] Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome).[2]In vitro studies have shown that menin is localized to the nucleus, possesses two functional nuclear localization signals, and inhibits transcriptional activation by JunD. However, the function of this protein is not known. Two messages have been detected on northern blots but the larger message has not been characterized. Two variants of the shorter transcript have been identified where alternative splicing affects the coding sequence. Five variants where alternative splicing takes place in the 5' UTR have also been identified.[1]

History

In 1988, researchers at Uppsala University Hospital and the Karolinska Institute in Stockholm mapped the MEN1 gene to the long arm of chromosome 11.[2] The gene was finally cloned in 1997.[3]

Genomics

The gene is located on long arm of chromosome 11 (11q13) between base pairs 64,570,985 and 64,578,765. It has 10 exons and encodes a 610-amino acid protein.

Over 1300 mutations have been reported to date (2010). The majority (>70%) of these are predicted to lead to truncated forms are scattered throughout the gene. Four - c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur in 4.5%, 2.7%, 2.6% and 2.5% of families.[4]

Clinical implications

The MEN1 phenotype is inherited via an autosomal-dominant pattern and is associated with neoplasms of the pituitary gland, the parathyroid gland, and the pancreas (the 3 "P"s). While these neoplasias are often benign (in contrast to tumours occurring in MEN2A), they are adenomas and, therefore, produce endocrine phenotypes. Pancreatic presentations of the MEN1 phenotype may manifest as Zollinger-Ellison syndrome.

MEN1 pituitary tumours are adenomas of anterior cells, typically prolactinomas or growth hormone-secreting. Pancreatic tumours involve the islet cells, giving rise to gastrinomas or insulinomas. In rare cases, adrenal cortex tumours are also seen.

Role in cancer

Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin resulting in the inability of MEN1 to act as a tumor suppressor gene.[5] Such mutations in MEN1 have been associated with defective binding of encoded menin to proteins implicated in genetic and epigenetic mechanisms.[6] Menin is a 621 amino acid protein associated with insulinomas[7] which acts as an adapter while also interacting with partner proteins involved in vital cell activities such as transcriptional regulation, cell division, cell proliferation, and genome stability. Insulinomas are neuroendocrine tumors of the pancreas with an incidence of 0.4 %[8] which usually are benign solitary tumors but 5-12 % of cases have distant metastasis at diagnosis.[9] These familial MEN-1 and sporadic tumors may arise either due to loss of heterozygosity or the chromosome region 11q13 where MEN1 is located, or due to presence of mutations in the gene.[10][11]

MEN1 mutations comprise mostly frameshift deletions or insertions, followed by nonsense, missense, splice-site mutations and either part or complete gene deletions resulting in disease pathology.[12] Frameshift and nonsense mutations result in a supposed inactive and truncated menin protein while splice-site mutations result in incorrectly spliced mRNA. Missense mutations of MEN1 are especially important as they result in a change to crucial amino acids needed in order to bind and interact with other proteins and molecules. As menin is located predominantly in the nucleus,[13] these mutations can impact the stability of the cell and may further affect functional activity or expression levels of the protein. Studies have also shown that single amino acid changes in genes involved in oncogenic disorders may result in proteolytic degradation leading to loss of function and reduced stability of the mutant protein; a common mechanism for inactivating tumor suppressor gene products.[14][15] MEN1 gene mutations and deletions also play a role in the development of hereditary and a subgroup of sporadic pituitary adenomas and were detected in approximately 5% of sporadic pituitary adenomas.[16] Consequently, alterations of the gene represent a candidate pathogenetic mechanism of pituitary tumorigenesis especially when considered in terms of interactions with other proteins, growth factors, oncogenes play a rule in tumorigenesis.

Although the exact function of MEN1 is not known, the Knudson "two-hit" hypothesis provides strong evidence that it is a tumor suppressor gene. Familial loss of one copy of MEN1 is seen In association with MEN-1 syndrome. Tumor suppressor carcinogenesis follows Knudson's "two-hit" model.[17] The first hit is a heterozygous MEN1 germline mutation either developed in an early embryonic stage and consequently present in all cells at birth for the sporadic cases, or inherited from one parent in a familial case. The second hit is a MEN1 somatic mutation, oftentimes a large deletion occurring in the predisposed endocrine cell and providing cells with the survival advantaged needed for tumor development.[18] The MEN-1 syndrome often exhibits tumors of parathyroid glands, anterior pituitary, endocrine pancreas, and endocrine duodenum. Less frequently, neuroendocrine tumors of lung, thymus, and stomach or non-endocrine tumors such as lipomas, angiofibromas, and ependymomas are observed neoplasms.[19]

In a study of 12 sporadic carcinoid tumors of the lung, five cases involved inactivation of both copies of the MEN1 gene. Of the five carcinoids, three were atypical and two were typical. The two typical carcinoids were characterized by a rapid proliferative rate with a higher mitotic index and stronger Ki67 positivity than the other typical carcinoids in the study. Consequently, the carcinoid tumors with MEN1 gene inactivation in the study were considered to be characterized by more aggressive molecular and histopathological features than those without MEN1 gene alterations.[20]

Interactions

MEN1 has been shown to interact with:

  • FANCD2,[21]
  • GFAP,[22]
  • JunD,[23]
  • NFKB1,[22]
  • MLL,[24]
  • RPA2,[25] and
  • VIM.[26]

References

1. ^1 {{cite web | title = Entrez Gene: MEN1 multiple endocrine neoplasia I| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4221| accessdate = }}
2. ^{{cite journal | vauthors = Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, Oberg K, Werner S, Nordenskjöld M | title = Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 5 | pages = 1968–72 | date = March 1990 | pmid = 1968641 | pmc = 53606 | doi = 10.1073/pnas.87.5.1968 }}
3. ^{{cite journal | vauthors = Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ | title = Positional cloning of the gene for multiple endocrine neoplasia-type 1 | journal = Science | volume = 276 | issue = 5311 | pages = 404–7 | date = April 1997 | pmid = 9103196 | doi = 10.1126/science.276.5311.404 }}
4. ^1 {{cite journal | vauthors = Thakker RV | title = Multiple endocrine neoplasia type 1 (MEN1) | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 24 | issue = 3 | pages = 355–70 | date = June 2010 | pmid = 20833329 | doi = 10.1016/j.beem.2010.07.003 | authorlink1 = Rajesh Thakker }}
5. ^{{cite journal | vauthors = Agarwal SK, Lee Burns A, Sukhodolets KE, Kennedy PA, Obungu VH, Hickman AB, Mullendore ME, Whitten I, Skarulis MC, Simonds WF, Mateo C, Crabtree JS, Scacheri PC, Ji Y, Novotny EA, Garrett-Beal L, Ward JM, Libutti SK, Richard Alexander H, Cerrato A, Parisi MJ, Santa Anna-A S, Oliver B, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ | title = Molecular pathology of the MEN1 gene | journal = Annals of the New York Academy of Sciences | volume = 1014 | pages = 189–98 | date = April 2004 | pmid = 15153434 | doi = 10.1196/annals.1294.020}}
6. ^{{cite journal | vauthors = Jyotsna VP, Malik E, Birla S, Sharma A | title = Novel MEN 1 gene findings in rare sporadic insulinoma--a case control study | journal = BMC Endocrine Disorders | volume = 15 | pages = 44 | date = 2015-01-01 | pmid = 26307114 | pmc = 4549893 | doi = 10.1186/s12902-015-0041-2 }}
7. ^{{cite journal | vauthors = Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ | title = Positional cloning of the gene for multiple endocrine neoplasia-type 1 | journal = Science | volume = 276 | issue = 5311 | pages = 404–7 | date = April 1997 | pmid = 9103196 | doi=10.1126/science.276.5311.404}}
8. ^{{cite journal | vauthors = Abu-Zaid A, Alghuneim LA, Metawee MT, Elkabbani RO, Almana H, Amin T, Azzam A | title = Sporadic insulinoma in a 10-year-old boy: a case report and literature review | journal = JOP | volume = 15 | issue = 1 | pages = 53–7 | date = January 2014 | pmid = 24413786 }}
9. ^{{cite journal | vauthors = Schussheim DH, Skarulis MC, Agarwal SK, Simonds WF, Burns AL, Spiegel AM, Marx SJ | title = Multiple endocrine neoplasia type 1: new clinical and basic findings | journal = Trends in Endocrinology and Metabolism | volume = 12 | issue = 4 | pages = 173–8 | date = 2001-06-01 | pmid = 11295574 | doi=10.1016/s1043-2760(00)00372-6}}
10. ^{{cite journal | vauthors = Thakker RV | title = Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) | journal = Molecular and Cellular Endocrinology | volume = 386 | issue = 1-2 | pages = 2–15 | date = April 2014 | pmc = 4082531 | doi = 10.1016/j.mce.2013.08.002 | pmid = 23933118 }}
11. ^{{cite journal | vauthors = Friedman E, Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB, Weinstein LS, McBride WO, Nakamura Y, Brandi ML | title = Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1 | journal = The New England Journal of Medicine | volume = 321 | issue = 4 | pages = 213–8 | date = July 1989 | pmid = 2568586 | doi = 10.1056/nejm198907273210402 }}
12. ^{{cite journal | vauthors = Lemos MC, Thakker RV | title = Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene | journal = Human Mutation | volume = 29 | issue = 1 | pages = 22–32 | date = January 2008 | pmid = 17879353 | doi = 10.1002/humu.20605 }}
13. ^{{cite journal | vauthors = Guru SC, Manickam P, Crabtree JS, Olufemi SE, Agarwal SK, Debelenko LV | title = Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene | journal = Journal of Internal Medicine | volume = 243 | issue = 6 | pages = 433–9 | date = June 1998 | pmid = 9681840 | doi=10.1046/j.1365-2796.1998.00346.x}}
14. ^{{cite journal | vauthors = Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL | title = Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription | journal = Cell | volume = 96 | issue = 1 | pages = 143–52 | date = January 1999 | pmid = 9989505 | doi=10.1016/s0092-8674(00)80967-8}}
15. ^{{cite journal | vauthors = Yaguchi H, Ohkura N, Tsukada T, Yamaguchi K | title = Menin, the multiple endocrine neoplasia type 1 gene product, exhibits GTP-hydrolyzing activity in the presence of the tumor metastasis suppressor nm23 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 41 | pages = 38197–204 | year = 2002 | pmid = 12145286 | doi = 10.1074/jbc.M204132200 }}
16. ^{{cite journal | vauthors = Zhuang Z, Ezzat SZ, Vortmeyer AO, Weil R, Oldfield EH, Park WS, Pack S, Huang S, Agarwal SK, Guru SC, Manickam P, Debelenko LV, Kester MB, Olufemi SE, Heppner C, Crabtree JS, Burns AL, Spiegel AM, Marx SJ, Chandrasekharappa SC, Collins FS, Emmert-Buck MR, Liotta LA, Asa SL, Lubensky IA | title = Mutations of the MEN1 tumor suppressor gene in pituitary tumors | journal = Cancer Research | volume = 57 | issue = 24 | pages = 5446–51 | date = December 1997 | pmid = 9407947 }}
17. ^{{cite journal | vauthors = Knudson AG | title = Antioncogenes and human cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 10914–21 | date = December 1993 | pmc = 47892 | pmid = 7902574 | doi=10.1073/pnas.90.23.10914}}
18. ^{{cite journal | vauthors = Marx SJ, Agarwal SK, Kester MB, Heppner C, Kim YS, Emmert-Buck MR, Debelenko LV, Lubensky IA, Zhuang Z, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Doppman JL, Alexander RH, Liotta LA, Collins FS, Chandrasekharappa SC, Spiegel AM, Burns AL | title = Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN1) | journal = Journal of Internal Medicine | volume = 243 | issue = 6 | pages = 447–53 | date = June 1998 | pmid = 9681842 | doi=10.1046/j.1365-2796.1998.00348.x}}
19. ^{{cite book | vauthors = Metz DC, Jensen RT, Bale AE, Skarulis MC, Eastman RC, Nieman L, Norton JA, Friedman E, Larsson C, Amorosi A, Brandi ML, Marx SJ | chapter = Multiple endocrine neoplasia type I. Clinical features and management | veditors = Bilezikian JP, Levine MA, Marcus, R | title = The Parathyroids | publisher = Raven Press Publishing Co | location = New York | pages = 591–646 | year = 1994 }}
20. ^{{cite journal | vauthors = Debelenko LV, Brambilla E, Agarwal SK, Swalwell JI, Kester MB, Lubensky IA, Zhuang Z, Guru SC, Manickam P, Olufemi SE, Chandrasekharappa SC, Crabtree JS, Kim YS, Heppner C, Burns AL, Spiegel AM, Marx SJ, Liotta LA, Collins FS, Travis WD, Emmert-Buck MR | title = Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung | journal = Human Molecular Genetics | volume = 6 | issue = 13 | pages = 2285–90 | date = December 1997 | pmid = 9361035 | doi = 10.1093/hmg/6.13.2285 }}
21. ^{{cite journal | vauthors = Jin S, Mao H, Schnepp RW, Sykes SM, Silva AC, D'Andrea AD, Hua X | title = Menin associates with FANCD2, a protein involved in repair of DNA damage | journal = Cancer Research | volume = 63 | issue = 14 | pages = 4204–10 | date = July 2003 | pmid = 12874027 | doi = }}
22. ^1 {{cite journal | vauthors = Heppner C, Bilimoria KY, Agarwal SK, Kester M, Whitty LJ, Guru SC, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL | title = The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation | journal = Oncogene | volume = 20 | issue = 36 | pages = 4917–25 | date = August 2001 | pmid = 11526476 | doi = 10.1038/sj.onc.1204529 }}
23. ^{{cite journal | vauthors = Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL | title = Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription | journal = Cell | volume = 96 | issue = 1 | pages = 143–52 | date = January 1999 | pmid = 9989505 | doi = 10.1016/S0092-8674(00)80967-8 }}
24. ^{{cite journal | vauthors = Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero DJ, Kitabayashi I, Herr W, Cleary ML | title = Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression | journal = Molecular and Cellular Biology | volume = 24 | issue = 13 | pages = 5639–49 | date = July 2004 | pmid = 15199122 | pmc = 480881 | doi = 10.1128/MCB.24.13.5639-5649.2004 }}
25. ^{{cite journal | vauthors = Sukhodolets KE, Hickman AB, Agarwal SK, Sukhodolets MV, Obungu VH, Novotny EA, Crabtree JS, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ | title = The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene | journal = Molecular and Cellular Biology | volume = 23 | issue = 2 | pages = 493–509 | date = January 2003 | pmid = 12509449 | pmc = 151531 | doi = 10.1128/MCB.23.2.493-509.2003 }}
26. ^{{cite journal | vauthors = Lopez-Egido J, Cunningham J, Berg M, Oberg K, Bongcam-Rudloff E, Gobl A | title = Menin's interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity | journal = Experimental Cell Research | volume = 278 | issue = 2 | pages = 175–83 | date = August 2002 | pmid = 12169273 | doi = 10.1006/excr.2002.5575 }}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Tsukada T, Yamaguchi K, Kameya T | title = The MEN1 gene and associated diseases: an update | journal = Endocrine Pathology | volume = 12 | issue = 3 | pages = 259–73 | year = 2002 | pmid = 11740047 | doi = 10.1385/EP:12:3:259 }}
  • {{cite journal | vauthors = Kong C, Ellard S, Johnston C, Farid NR | title = Multiple endocrine neoplasia type 1Burin from Mauritius: a novel MEN1 mutation | journal = Journal of Endocrinological Investigation | volume = 24 | issue = 10 | pages = 806–10 | date = November 2001 | pmid = 11765051 | doi = 10.1007/bf03343931 }}
  • {{cite journal | vauthors = Thakker RV | title = Multiple endocrine neoplasia | journal = Hormone Research | volume = 56 Suppl 1 | issue = | pages = 67–72 | year = 2002 | pmid = 11786689 | doi = 10.1159/000048138 }}
  • {{cite journal | vauthors = Stowasser M, Gunasekera TG, Gordon RD | title = Familial varieties of primary aldosteronism | journal = Clinical and Experimental Pharmacology & Physiology | volume = 28 | issue = 12 | pages = 1087–90 | date = December 2001 | pmid = 11903322 | doi = 10.1046/j.1440-1681.2001.03574.x }}
  • {{cite journal | vauthors = Kameya T, Tsukada T, Yamaguchi K | title = Recent advances in MEN1 gene study for pituitary tumor pathogenesis | journal = Frontiers of Hormone Research | volume = 32 | issue = | pages = 265–91 | year = 2004 | pmid = 15281352 | doi = 10.1159/000079050 | isbn = 3-8055-7740-0 | series = Frontiers of Hormone Research }}
  • {{cite journal | vauthors = Balogh K, Rácz K, Patócs A, Hunyady L | title = Menin and its interacting proteins: elucidation of menin function | journal = Trends in Endocrinology and Metabolism | volume = 17 | issue = 9 | pages = 357–64 | date = November 2006 | pmid = 16997566 | doi = 10.1016/j.tem.2006.09.004 }}
  • {{cite journal | vauthors = Lytras A, Tolis G | title = Growth hormone-secreting tumors: genetic aspects and data from animal models | journal = Neuroendocrinology | volume = 83 | issue = 3-4 | pages = 166–78 | year = 2006 | pmid = 17047380 | doi = 10.1159/000095525 }}
{{refend}}

External links

  • [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=men1 GeneReviews/NIH/NCBI/UW entry on Multiple Endocrine Neoplasia Type 1]
  • MEN1 gene variant database
  • {{MeshName|MEN1+protein,+human}}
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