Homozygous loss of menin is well tolerated in liver, a tissue not affected in MEN1.
Most tumor suppressor genes show a widespread pattern of expression, yet individuals with germline, heterozygous loss of function of such genes develop tumors in a restricted set of tissues. This paradox has generated a multitude of speculative hypotheses. The gene for multiple endocrine neoplasia type I (MEN1) encodes a ubiquitously expressed tumor suppressor of unknown function called menin. Humans and mice with germline, heterozygous loss-of-function mutations in the MEN1 gene almost always develop at least one endocrine tumor by late adulthood, and examination of those tumors invariably reveals loss of the wild-type allele. To investigate the paradox of tissue-specific tumor phenotype in MEN1, mice homozygous for an Men1 gene with exons 3-8 flanked by loxP sites were bred to transgenic mice expressing cre from the albumin promoter. This strategy allowed us to generate mice with homozygous deletion of the Men1 gene in liver, a tissue not normally predisposed to developing tumors in humans or mice with heterozygous MEN1 loss-of-function mutations. Livers that were completely null for menin expression appeared entirely normal and remained tumor free until late adulthood. These results argue against certain hypotheses previously proposed for the tissue specificity of tumor suppressor genes and provide insights to the mechanism of tissue specificity in MEN1.
Scacheri
Peter C
PC
National Human Genome Research Institute, National Institutes of Health, Bldg 31, Room 4B09, 31 Center Drive, Bethesda, Maryland 20892, USA.
Crabtree
Judy S
JS
Kennedy
Alyssa L
AL
Swain
Gary P
GP
Ward
Jerrold M
JM
Marx
Stephen J
SJ
Spiegel
Allen M
AM
Collins
Francis S
FS
D000418:Albumins / Q000378:metabolism; D000818:Animals; D019426:Integrases / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D000418:Albumins; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; C045073:Cre recombinase; D019426:Integrases