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Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.


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.

SUBMITTER: Milne TA 

PROVIDER: S-EPMC545577 | biostudies-literature | 2005 Jan

REPOSITORIES: biostudies-literature

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Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.

Milne Thomas A TA   Hughes Christina M CM   Lloyd Ricardo R   Yang Zhaohai Z   Rozenblatt-Rosen Orit O   Dou Yali Y   Schnepp Robert W RW   Krankel Cynthia C   Livolsi Virginia A VA   Gibbs Denise D   Hua Xianxin X   Roeder Robert G RG   Meyerson Matthew M   Hess Jay L JL  

Proceedings of the National Academy of Sciences of the United States of America 20050107 3


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 r  ...[more]

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