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

doi:10.1073/pnas.0408836102

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

Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):749-54. doi: 10.1073/pnas.0408836102. Epub 2005 Jan 7.

Authors

Thomas A Milne¹, 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

Affiliation

¹ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Carrier Proteins / genetics
Cell Cycle Proteins / genetics
Cell Line
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p18
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology*
Gene Expression Regulation*
Histone-Lysine N-Methyltransferase
Humans
Intracellular Signaling Peptides and Proteins / genetics
Myeloid-Lymphoid Leukemia Protein
Open Reading Frames
Promoter Regions, Genetic
Proto-Oncogene Proteins / physiology*
Proto-Oncogenes / genetics
Proto-Oncogenes / physiology*
Transcription Factors / genetics
Transcription Factors / physiology*
Transcriptional Activation
Transfection
Tumor Suppressor Proteins / genetics

Substances

CDKN1B protein, human
CDKN2C protein, human
Carrier Proteins
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p18
DNA-Binding Proteins
Intracellular Signaling Peptides and Proteins
KMT2A protein, human
MEN1 protein, human
Proto-Oncogene Proteins
Transcription Factors
Tumor Suppressor Proteins
Cyclin-Dependent Kinase Inhibitor p27
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Cyclin-Dependent Kinases