The MEN1 gene is a likely tumor suppressor gene because tumors in multiple endocrine neoplasia type 1 (MEN1) show loss of heterozygosity (LOH) at this locus and because sporadic tumors of the same tissues also show 11q13 LOH implicating this gene through a similar mechanism. We have contributed to 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 it causes nonendocrine tumors (angiofibroma, collagenoma, and leiomyoma). We find germline mutations in 90-95% of probands with familial MEN1 or with sporadic MEN1. We have identified an MEN1 variant in three large families with infrequent gastrinoma. In contrast, probands with familial isolated hyperparathyroidism have not shown MEN1 mutations. We will continue to explore these and other states for germline MEN1 mutations. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. We will also determine the spectrum of pathologic states that MEN1 gene contributes to through mutation and other mechanisms. We have also initiated studies on the expression and actions of the encoded menin RNA and protein. The gene has been expressed in E. Coli and mammalian cells and will be overexpressed in insect cells. And vector constructs are being developed to express mutant forms. The MEN1-encoded protein is called """"""""menin"""""""". We have identified menin interaction with the nuclear transcription factors junD, NF-kappaB, and other interactions are being sought. Other groups have found menin also in a COMPASS-like complex. These studies should help identify its biochemical activities. Heterozygous Men1 knockout in the mouse is a useful model under evaluation. Menin inactivation shifts junD from growth suppressor to growth promoter, representing the first plausible pathway for menin tumorigenesis. Another type of pathway arises from our observations that menin binds directly or indirectly to hundreds or even thousands of sites in chromatin.
Showing the most recent 10 out of 37 publications
