Kaji H, Canaff L, Lebrun J J, Goltzman D, Hendy G N
Calcium Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, QC, Canada H3A 1A1.
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3837-42. doi: 10.1073/pnas.061358098. Epub 2001 Mar 13.
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.
1型多发性内分泌腺瘤病（MEN1）是一种常染色体显性疾病，其特征为甲状旁腺、胰岛和垂体前叶的内分泌肿瘤。MEN1基因编码一种名为menin的核蛋白。在MEN1携带者中，失活突变会产生一种截短的产物，这与menin作为肿瘤抑制基因的作用一致。然而，menin在肿瘤发生中的作用及其生理功能尚不清楚。在此，我们表明反义RNA使menin失活可拮抗转化生长因子β介导的细胞生长抑制。Menin与Smad3相互作用，反义menin通过在特定转录调控位点抑制Smad3/4与DNA的结合，抑制转化生长因子β诱导的和Smad3诱导的转录活性。这些结果提示了一种由menin失活导致肿瘤发生的机制。
