Menin induces apoptosis in murine embryonic fibroblasts.
Multiple endocrine neoplasia type I (MEN1) is a hereditary tumor syndrome characterized by multiple endocrine and occasionally non-endocrine tumors. The tumor suppressor gene Men1, which is frequently mutated in MEN1 patients, encodes the nuclear protein menin. Although many tumor suppressor genes are involved in the regulation of apoptosis, it is unclear whether menin facilitates apoptosis. Here we show that ectopic overexpression of menin via adenoviruses induces apoptosis in murine embryonic fibroblasts. The induction of apoptosis depends on Bax and Bak, two proapoptotic proteins. Moreover, loss of menin expression compromises apoptosis induced by UV irradiation and tumor necrosis factor-alpha (TNF-alpha), whereas complementation of menin-null cells with menin restores sensitivity to UV- and TNF-alpha-induced apoptosis. Interestingly, loss of menin reduces the expression of procaspase 8, a critical protease that is essential for apoptosis induced by death-related receptors, whereas complementation of the menin-null cells up-regulates the expression of procaspase 8. Furthermore, complementation of menin-null cells with menin increases the activation of caspase 8 in response to TNF-alpha treatment. These results suggest a proapoptotic function for menin that may be important in suppressing the development of MEN1.
Schnepp
Robert W
RW
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Mao
Hua
H
Sykes
Stephen M
SM
Zong
Wei-Xing
WX
Silva
Albert
A
La
Ping
P
Hua
Xianxin
X
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D005816:Genetic Complementation Test; D005822:Genetic Vectors; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009707:Nucleosomes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014343:Trypan Blue / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
D017304:Annexin A5; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009707:Nucleosomes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D004247:DNA; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D014343:Trypan Blue