The MEN1 gene is a likely tumor suppressor gene because tumors in multiple endocrine neoplasia type 1 (MEN1) show loss of heterozygosity (LOH) about the MEN1 locus and because sporadic tumors of the same tissues also show 11q13 LOH implicating loss of this gene through a similar mechanism. We have helped to lead an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We have proven that MEN1 inactivation causes nonendocrine tumors (angiofibroma, collagenoma, and leiomyoma) in MEN1. We find germline mutations in 70-80% of probands with the rare syndromes of familial MEN1 or with sporadic MEN1. Pobands with familial isolated hyperparathyroidism have rarely shown MEN1 mutations. We will continue to explore these and other MEN1-like states with rare germline MEN1 mutations. The definition of subgroups that are deficient of MEN1 mutation has promoted the identification of known genes (CASR, p27) and newly identified genes (HRPT2, AIP, p15, p18, p27) in MEN1-like states. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. Its role in common tumors predicts that clarification of its molecular pathway will offer new chances for interventions in many common variety tumors. A mouse strain was engineered with MEN1 heterozygous inactivation. Loss of the normal allele of MEN1 caused giant hyperplasia of pancreatic islets. This is a polyclonal process without loss of menin. This is a phenotype from loss of one allele of MEN1 or haploinsufficiency. It is likely a tumor precursor stage and it has implications about islet development.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$252,614
Indirect Cost
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State
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Simonds, William F; Varghese, Sarah; Marx, Stephen J et al. (2012) Cushing's syndrome in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 76:379-86
Yavuz, Sahzene; Simonds, William F; Weinstein, Lee S et al. (2012) Sleeping parathyroid tumor: rapid hyperfunction after removal of the dominant tumor. J Clin Endocrinol Metab 97:1834-41
Marx, Stephen J (2011) Hyperparathyroid genes: sequences reveal answers and questions. Endocr Pract 17 Suppl 3:18-27
Wang, Yan; Ozawa, Atsushi; Zaman, Shadia et al. (2011) The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Res 71:371-82
Agarwal, Sunita K; Mateo, Carmen M; Marx, Stephen J (2009) Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab 94:1826-34
Shen, H-C Jennifer; He, Mei; Powell, Anathea et al. (2009) Recapitulation of pancreatic neuroendocrine tumors in human multiple endocrine neoplasia type I syndrome via Pdx1-directed inactivation of Men1. Cancer Res 69:1858-66