Endocrine Abstracts

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of anterior pituitary, pancreatic islet and parathyroid tumours. Mice (Men1^+/−) deleted for an MEN1 allele develop these tumours. The MEN1 gene encodes a 610 amino acid protein that has been reported to upregulate caspase 8 expression and promote apoptosis. To characterize the functional effects of menin loss in vivo, we assessed apoptosis using a TUNEL assay utilizing sections from eight pituitary tumours of Men1^+/− mice and eight normal pituitaries from Men1^+/+ (wild-type) littermates. This demonstrated a significant increase in apoptotic cells in the Men1^+/− pituitary tumours when compared to Men1^+/+ normal pituitaries (0.22±0.03 vs 0.12±0.03%, P<0.02). To gain mechanistic insights into the role of menin in apoptosis, we determined the cDNA expression profile of pituitary tumours from five Men1^+/− mice and in normal pituitaries from five Men1^+/+ littermates by extracting total RNA and by hybridizing it to Affymetrix Mouse Genome arrays. Pituitary tumours were found to have significant alterations of several anti-apoptotic pathway components including down-regulation of B-cell leukemia/lymphoma 2 (Bcl2) and neuronal apoptosis inhibitory proteins 2 and 5 (Naip2, Naip5) (−2.7-, −2.3- and −2.1-fold respectively, FDR<0.05) and up-regulation of Kirsten rat sarcoma viral oncogene homolog (Kras) and surviving (Birc5) (+1.9- and +2.8-fold respectively, FDR<0.05). We have initially focused on investigating Bcl2, and confirmed by quantitative reverse-transcriptase PCR that its expression is 2.3-fold lower (P<0.02), in Men1^+/− pituitary tumours when compared to Men1^+/+ normal pituitaries. Thus, these studies, which reveal an in vivo role of menin in the regulation of apoptosis that involves the Bcl2 gene, open the way for further investigation of the interaction between the apoptotic and tumourigenic pathways in the aetiology of pituitary tumours.