The Effect And Clinical Significance Of TGF-β On The Inhibition Of Menin To Parathyroid Tumors

Background Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease predisposed by heterozygous germline mutations in the MEN1 tumor suppressor gene. Biallelic loss of MEN1 resulting from small mutation and/or loss of heterozygosity occurs in a large tissue spectrum of MEN1 tumors or non-hereditary tumors. Mouse models of MEN1 underexpression or overexpression have also supported the tumor-suppressor effect of the MEN1 gene. Menin, the 610-amino-acid protein encoded by MEN1, is expressed ubiquitously and found predominantly in the nucleus. Sequence analyses do not reveal motifs of known function other than two nuclear localization sequences. Menin has been found to partner in vitro with a variety of proteins that comprise transcription factors, DNA processing factors, DNA repair proteins, and cytoskeletal proteins. The diverse functions of menin interactors suggest roles for menin in multiple biological pathways. Inactivation of menin switches its JunD partner from a downstream action of growth suppression to growth promotion. This is a plausible mechanism for menin tumorigenesis. 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. In cultured parathyroid cells from uremic hemodialysis patients, in which the menin signaling pathways are probably still intact, menin inactivation achieved by menin antisense oligonucleotides leads to loss of TGF-beta inhibition of parathyroid cell proliferation and parathyroid hormone (PTH) secretion. Moreover, TGF-beta does not affect the proliferation and PTH production of parathyroid cells from multiple endocrine neoplasia type 1 (MEN1) patients.Objective To explore the fuction and clinical significance of TGF-βon the inhibition of menin to parathyroid adnoma.Method The expression of the Menin protein and TGF-βwere determined by immunohistochemistry in 7 cases of normal parathyroid tissue, 12 cases of parathyroid proliferation tissue and 43 cases of parathyroid adnoma tissue.Results The expression of Menin protein was significantly different between normal parathyroid and parathyroid adnoma ( p<0.05), and was not significantly different between normal parathyroid and parathyroid proliferation ( p>0.05). The expression of TGF-βwas not significantly different among the three groups ( p>0.05). But the expression of Menin was significantly related to that of TGF-βin the adnoma group.Conclusions Firstly, the inactivation of Menin protein would be play an important role in the development of parathyroid tumor; Secondly, derangements of the TGF-βpathyway due to menin mutation would be also implicated in the development of parathyroid tumor.