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Menin is a 70-kDa protein encoded by MEN1, the tumor suppressor gene disrupted in multiple endocrine neoplasia type 1. In a yeast two-hybrid system based on reconstitution of Ras signaling, menin was found to interact with the 32-kDa subunit (RPA2) of replication protein A (RPA), a heterotrimeric protein required for DNA replication, recombination, and repair. The menin-RPA2 interaction was confirmed in a conventional yeast two-hybrid system and by direct interaction between purified proteins. Menin-RPA2 binding was inhibited by a number of menin missense mutations found in individuals with multiple endocrine neoplasia type 1, and the interacting regions were mapped to the N-terminal portion of menin and amino acids 43 to 171 of RPA2. This region of RPA2 contains a weak single-stranded DNA-binding domain, but menin had no detectable effect on RPA-DNA binding in vitro. Menin bound preferentially in vitro to free RPA2 rather than the RPA heterotrimer or a subcomplex consisting of RPA2 bound to the 14-kDa subunit (RPA3). However, the 70-kDa subunit (RPA1) was coprecipitated from HeLa cell extracts along with RPA2 by menin-specific antibodies, suggesting that menin binds to the RPA heterotrimer or a novel RPA1-RPA2-containing complex in vivo. This finding was consistent with the extensive overlap in the nuclear localization patterns of endogenous menin, RPA2, and RPA1 observed by immunofluorescence.
Pubmed ID: 12509449 RIS Download
Mesh terms: Animals | Bacterial Proteins | Blotting, Western | Cell Line | Cell Nucleus | Chromatography, Gel | DNA | DNA Damage | DNA, Complementary | DNA-Binding Proteins | G1 Phase | Glutathione Transferase | HeLa Cells | Humans | Mice | Microscopy, Fluorescence | Multiple Endocrine Neoplasia | Mutation, Missense | Neoplasm Proteins | Plasmids | Precipitin Tests | Protein Binding | Protein Structure, Tertiary | Proto-Oncogene Proteins | Recombinant Proteins | Replication Protein A | S Phase | Transfection | Two-Hybrid System Techniques
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