Inactivation of Menin, A Smad3-Interacting Protein, Blocks Transforming Growth Factor Type β Signaling

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by endocrine tumors of parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene encodes a nuclear protein called menin. In MEN1 carriers inactivating mutations give rise to a truncated product co...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-03, Vol.98 (7), p.3837-3842
Main Authors: Kaji, Hiroshi, Canaff, Lucie, Lebrun, Jean-Jacques, Goltzman, David, Hendy, Geoffrey N.
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - drug effects
Animals
Antibodies
Biological Sciences
Cell Division - drug effects
Cell growth
Cell lines
CHO Cells
Complementary DNA
COS Cells
Cricetinae
DNA
DNA - drug effects
DNA - metabolism
DNA, Complementary - biosynthesis
DNA-Binding Proteins - metabolism
DNA-Binding Proteins - physiology
Endocrine cells
Hep G2 cells
Humans
MEN1 gene
menin
multiple endocrine neoplasia 1
Multiple endocrine neoplasia type 1
Neoplasm Proteins - antagonists & inhibitors
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Pituitary Gland, Anterior - cytology
Pituitary Gland, Anterior - physiology
Proto-Oncogene Proteins
Rats
RNA, Antisense - pharmacology
Signal Transduction
Smad3 Protein
Smad4 protein
Trans-Activators - metabolism
Trans-Activators - physiology
Transcriptional Activation - drug effects
Transforming Growth Factor beta - physiology
Tumor Cells, Cultured
Tumors
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Summary:Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by endocrine tumors of parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene encodes a nuclear protein called menin. In MEN1 carriers inactivating mutations give rise to a truncated product consistent with menin acting as a tumor suppressor gene. However, the role of menin in tumorigenesis and its physiological functions are not known. Here, we show that menin inactivation by antisense RNA antagonizes transforming growth factor type β-mediated cell growth inhibition. Menin interacts with Smad3, and antisense menin suppresses transforming growth factor type β-induced and Smad3-induced transcriptional activity by inhibiting Smad3/4-DNA binding at specific transcriptional regulatory sites. These results implicate a mechanism of tumorigenesis by menin inactivation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.061358098