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Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression

Abstract

Menin is encoded by the tumor suppressor gene MEN1 that is mutated in patients with an inherited tumor syndrome, multiple endocrine neoplasia type 1 (MEN1). Although menin is a nuclear protein and directly binds to DNA through its nuclear localization signals (NLSs), the precise role for each of the NLSs in nuclear translocation and gene expression remains to be elucidated. Here, we show that point mutations in three individual NLSs, NLS1, NLS2, and a novel accessory NLS, NLSa, do not block nuclear translocation, but compromise the ability of menin to repress expression of the endogenous insulin-like growth factor binding protein-2 (IGFBP-2) gene. This repression is not released by an inhibitor of histone deacetylases. Although subtle mutations in menin NLSs do not affect menin association with chromatin, they abolish menin binding to the IGFBP-2 promoter in vivo. Furthermore, each of the NLSs is also crucial for menin-mediated induction of caspase 8 expression. Together, these results suggest that menin may act as a scaffold protein in coordinating activation and repression of gene transcription and that its NLSs play a more important role in controlling gene transcription than merely targeting menin into the nucleus.

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Acknowledgements

This work is in part supported by NIH Grants (R01 CA113962 and R01 CA100912 to XH) and a scholar award from Rita Allen Foundation (to XH). We thank Eyad Kanawati and Xiang Yu for excellent technical assistance. We appreciate the valuable suggestions from the reviewers that strengthened the manuscript.

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Correspondence to X Hua.

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La, P., Desmond, A., Hou, Z. et al. Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. Oncogene 25, 3537–3546 (2006). https://doi.org/10.1038/sj.onc.1209400

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