Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors
Thomas A. Milne,Christina M. Hughes,Ricardo V. Lloyd,Zhaohai Yang,Orit Rozenblatt-Rosen,Yali Dou,Robert W. Schnepp,Cynthia Krankel,Virginia A. LiVolsi,Denise Gibbs,Xianxin Hua,Robert G. Roeder,Matthew Meyerson,Jay L. Hess +13 more
TL;DR: It is shown that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c and plays a central role in menin's activity as a tumor suppressor.
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Abstract: Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c . Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.
MEN1
methyltransferase
tumor suppressor
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Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways
Akihiko Yokoyama,Francesca Ficara,Mark Murphy,Christian Meisel,Alpana Naresh,Issay Kitabayashi,Michael L. Cleary +6 more
TL;DR: The data demonstrate that the dissociated MLL subunits are subjected to distinct degradation pathways and thus not likely to have separate functions unless the degradation mechanisms are inhibited.
Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation
TL;DR: Reports on exceptional clinical presentations of multiple endocrine neoplasia type 1 are discussed, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype–phenotype correlation.
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Genetics of Acromegaly and Gigantism.
Anna Bogusławska,Márta Korbonits +1 more
TL;DR: A review of the most genetically determined pituitary tumour types can be found in this article, where the authors focus on germline and somatic mutations predisposing to acromegaly and gigantism.
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Reconstituted expression of menin in Men1-deficient mouse Leydig tumour cells induces cell cycle arrest and apoptosis
Nader Hussein,Huguette Casse,Sandra Fontanière,Anne-Marie Morera,Marie J. Asensio,Skander Bakeli,Jie L. Lu,Isabelle Coste,Nathalie di Clemente,Philippe Bertolino,Chang X. Zhang +10 more
TL;DR: The importance of menin expression in cell cycle and cell survival control in endocrine cells is highlighted, and insights into the mechanisms of tumour suppression by menin in related endocrine tumours are provided.
39
Cell lineage-specific interactions between Men1 and Rb in neuroendocrine neoplasia
TL;DR: It is demonstrated that, depending on cell lineage context, combined Men1 and Rb deficiency may be either redundant or detrimental to neoplastic growth.
38
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Positional Cloning of the Gene for Multiple Endocrine Neoplasia-Type 1
Settara C. Chandrasekharappa,Siradanahalli C. Guru,Pachiappan Manickam,Shodimu Emmanuel Olufemi,Francis S. Collins,Michael R. Emmert-Buck,Larisa V. Debelenko,Zhengping Zhuang,Irina A. Lubensky,Lance A. Liotta,Judy S. Crabtree,Yingping Wang,Bruce A. Roe,Jane M. Weisemann,Mark S. Boguski,Sunita K. Agarwal,Mary Beth Kester,Young Sik Kim,Christina Heppner,Qihan Dong,Allen M. Spiegel,A. Lee Burns,Stephen J. Marx +22 more
TL;DR: The identification of MEN1 will enable improved understanding of the mechanism of endocrine tumorigenesis and should facilitate early diagnosis of multiple endocrine neoplasia-type 1.
MLL targets SET domain methyltransferase activity to Hox gene promoters.
Thomas A. Milne,Scott D. Briggs,Hugh W. Brock,Mary Ellen Martin,Denise Gibbs,C. David Allis,Jay L. Hess +6 more
TL;DR: It is shown that MLL regulates target Hox gene expression through direct binding to promoter sequences and the MLL SET domain is a histone H3 lysine 4-specific methyltransferase whose activity is stimulated with acetylated H3 peptides.
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Principles of Tumor Suppression
TL;DR: It is recognized that tumor suppressor genes regulate diverse cellular activities, including cell cycle checkpoint responses, detection and repair of DNA damage, protein ubiquitination and degradation, mitogenic signaling, cell specification, differentiation and migration, and tumor angiogenesis.
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