Endocrine Abstracts

Menin is the product of the multiple endocrine neoplasia type 1 (MEN1) gene which when inactivated causes an autosomal dominant disorder characterized by tumors of the parathyroids, endocrine pancreas and anterior pituitary.

We identified an MEN1 splice-site mutation leading to a menin Δ(184–218) mutant having an in-frame deletion of 35 amino acids, but otherwise of wild-type sequence. The transfected mutant was well expressed, and like wild-type menin, interacted directly with the transcriptional regulators JunD and NF-κB and inhibited their activities. However, the mutant had lost the normal interaction with Smad3 and was defective in mediating TGF-β-stimulated Smad3 transcriptional activity, stimulation of the cyclin dependent kinase inhibitors (CDKIs), p15 and p21, and cytostatic activity. Thus the mutant was stable, had selective loss of TGF-β signaling and growth inhibition and, importantly, identified the menin/Smad3 interacting region on a homology model of the human menin structure. These studies suggest the menin/Smad3 interface as a potential therapeutic target.

We functionally characterized a panel of 16 menin missense mutants, including W423R and S443Y identified in new MEN1 families and that are poorly expressed. Proteasome inhibitors, MG132 and PS-341, and inhibition of the chaperone, heat shock protein 70 (Hsp70), or the ubiquitin ligase, COOH-terminus of Hsp70-interacting protein (CHIP), by specific siRNAs, restored the levels of the mutants whereas that of wild-type menin was unaffected. Inhibition of CHIP restored the ability of mutants to mediate normal functions of menin – TGF-β upregulation of p15 and p21, as well as TGF-β inhibition of cell proliferation. Potentially, targeting specific components of the proteasome chaperone pathway could be beneficial in treating a subset of MEN1 cases.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.