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PMID:15640349
| Citation |
Milne, TA, Hughes, CM, Lloyd, R, Yang, Z, Rozenblatt-Rosen, O, Dou, Y, Schnepp, RW, Krankel, C, Livolsi, VA, Gibbs, D, Hua, X, Roeder, RG, Meyerson, M and Hess, JL (2005) Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl. Acad. Sci. U.S.A. 102:749-54 |
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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. |
| Links |
PubMed PMC545577 Online version:10.1073/pnas.0408836102 |
| Keywords |
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; 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 |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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See also
References
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