Menin Interacts with the AP1 Transcription Factor JunD and Represses JunD-Activated Transcription

Abstract

MEN1 is a tumor suppressor gene that encodes a 610 amino acid nuclear protein (menin) of previously unknown function. Using a yeast two-hybrid screen with menin as the bait, we have identified the transcription factor JunD as a direct menin-interacting partner. Menin did not interact directly with other Jun and Fos family members. The menin-JunD interaction was confirmed in vitro and in vivo. Menin repressed transcriptional activation mediated by JunD fused to the Gal4 DNA-binding domain from a Gal4 responsive reporter, or by JunD from an AP1-responsive reporter. Several naturally occurring and clustered MEN1 missense mutations disrupted menin interaction with JunD. These observations suggest that menin's tumor suppressor function involves direct binding to JunD and inhibition of JunD activated transcription.

A murine ATFa-associated factor with transcriptional repressing activity

“…It is possible however that, depending on the assortment of promoter-bound factors, the level of transcriptional inhibition may vary. Similar moderate extents of repression (about threefold) have also been observed in the case of the unrelated tumour suppressor Menin which directly binds to JunD, thereby controlling JunD-activated transcription (Agarwal et al, 1999). Although the detailed mechanism of Menin function is presently unknown, impairment of its JunD binding capacity has dramatic consequences leading to cell transformation such as in multiple endocrine neoplasia (Jensen, 1999;Wenbin et al, 1999).…”

JunB and JunD Regulate Human Heme Oxygenase-1 Gene Expression in Renal Epithelial Cells

“…1, is located at approximately Ϫ4.0 kb from the transcriptional start site of the HO-1 promoter. We used antibodies to c-Jun, JunB, JunD, Nrf2 and USF1, as well as Menin, a tumor suppressor nuclear protein capable of interacting with JunD (53). The results of these analyses are shown in Fig.…”

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

“…Recent progress in studying the function of menin suggests that menin has diverse functions, including regulation of gene transcription (Agarwal et al, 1999;Kaji et al, 2001;Lin and Elledge, 2003;Hughes et al, 2004;La et al, 2004a;Schnepp et al, 2004b), cell proliferation (Kim et al, 1999;Kaji et al, 2001;La et al, 2004b;Ratineau et al, 2004;Schnepp et al, 2004a), apoptosis (Sayo et al, 2002;Schnepp et al, 2004b) and genome stability (Scappaticci et al, 1992;Jin et al, 2003;Busygina et al, 2004). Menin is primarily a nuclear protein and possesses two classic nuclear localization signals, NLS1 and NLS2 (Guru et al, 1998).…”

“…Typical NLSs consist of multiple positively charged amino-acid residues (Moroianu, 1999), and these basic residues specifically bind to a soluble transport receptor complex comprising importin a and importin b (Komeili and O'Shea, 2001), leading to translocation into the nucleus. As menin associates with chromatin and nuclear matrix (Jin et al, 2003), directly binds double-stranded DNA (dsDNA) , and regulates gene expression (Agarwal et al, 1999;Kaji et al, 2001;Lin and Elledge, 2003;Hughes et al, 2004;La et al, 2004a;Schnepp et al, 2004b), its nuclear localization should be essential for its role in regulation of gene transcription.…”