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

Thomas A. Milne, Christina M. Hughes, Ricardo 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

Research output: Contribution to journalArticle

330 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)749-754
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number3
DOIs
StatePublished - Jan 18 2005
Externally publishedYes

Keywords

  • Men1
  • Methyltransferase
  • Tumor suppressor

ASJC Scopus subject areas

  • General

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  • Cite this

    Milne, T. A., Hughes, C. M., Lloyd, R., Yang, Z., Rozenblatt-Rosen, O., Dou, Y., Schnepp, R. W., Krankel, C., LiVolsi, V. A., Gibbs, D., Hua, X., Roeder, R. G., Meyerson, M., & Hess, J. L. (2005). Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 102(3), 749-754. https://doi.org/10.1073/pnas.0408836102