Menin-mediated caspase 8 expression in suppressing multiple endocrine neoplasia type 1.
Multiple endocrine neoplasia type 1 (MEN1) is a familial tumor syndrome linked to mutation of the MEN1 gene, which encodes a tumor suppressor, menin. We previously reported that menin up-regulates the caspase 8 expression and promotes TNF-alpha-induced apoptosis. However, it remains unclear how menin up-regulates caspase 8 expression and whether menin-mediated caspase 8 expression plays a role in repressing MEN1 development. Here we show that menin binds the 5'-untranslated region (5'-UTR) of the Caspase 8 locus in vivo and activates transcription of a reporter gene through the 5'-UTR. Menin directly binds the 5'-UTR in a sequence-independent manner in vitro. Moreover, Men1 ablation in cells reduces acetylation of histones H3 and H4 at the 5'-UTR of the caspase 8 locus bound by menin in vivo. Notably, the MEN1-derived menin point mutants lose their ability to bind the caspase 8 locus and fail to induce caspase 8 expression and TNF-alpha-mediated apoptosis. Consistent with these observations, the expression level of caspase 8 is markedly reduced in insulinomas from Men1(+/-) mice. Together, our results indicate that menin enhances the caspase 8 expression by binding the caspase 8 locus, and suggest that menin suppresses MEN1 tumorigenesis, at least in part, by up-regulating caspase 8 expression.
La
Ping
P
Abramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Yang
Yuqing
Y
Karnik
Satyajit K
SK
Silva
Albert C
AC
Schnepp
Robert W
RW
Kim
Seung K
SK
Hua
Xianxin
X
D020121:5' Untranslated Regions / Q000378:metabolism; D000818:Animals; D053181:Caspase 8 / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000166:cytology; D004926:Escherichia coli / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D017930:Genes, Reporter; D006579:Heterozygote; D006801:Humans; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism*; D010957:Plasmids; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
D020121:5' Untranslated Regions; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D008156:Luciferases; D053181:Caspase 8