Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta 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 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 beta-mediated cell growth inhibition. Menin interacts with Smad3, and antisense menin suppresses transforming growth factor type beta-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.
Calcium Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, QC, Canada H3A 1A1.
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Kaji
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Canaff
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Lebrun
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Goltzman
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Hendy
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000502:physiology; D011518:Proto-Oncogene Proteins; D016372:RNA, Antisense / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016372:RNA, Antisense; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D004247:DNA