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

被引:356
作者
Milne, TA
Hughes, CM
Lloyd, R
Yang, ZH
Rozenblatt-Rosen, O
Dou, YL
Schnepp, RW
Krankel, C
LiVolsi, VA
Gibbs, D
Hua, XX
Roeder, RG
Meyerson, M
Hess, JL
机构
[1] Univ Penn, Sch Med, Dept Pathol & Lab Med, Stellar Chance Labs 413B, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Dept Canc Biol, Philadelphia, PA 19104 USA
[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[6] Mayo Clin & Mayo Fdn, Coll Med, Dept Pathol, Rochester, MN 55905 USA
[7] Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10021 USA
关键词
MEN1; methyltransferase; tumor suppressor;
D O I
10.1073/pnas.0408836102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 (MILL) 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 p27(Kip1) and p18(Ink4c). Menin activates transcription by means of a mechanism involving recruitment of MILL to the p27(Kip1) and p18(Ink4c) promoters and coding regions. Loss of function of either MILL or menin results in down-regulation of p27(KiP1) and p18(Ink4c) expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MILL plays a central role in menin's activity as a tumor suppressor.
引用
收藏
页码:749 / 754
页数:6
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