Reduction of menin expression enhances cell proliferation and is tumorigenic in intestinal epithelial cells.
Menin, the product of the tumor suppressor gene MEN1, is widely expressed in mammalian endocrine and non-endocrine tissues, including intestine. Its known abundant expression in several types of cells with high proliferative capacity led us to investigate the physiological function of the protein menin in intestinal epithelium, one of the most rapidly growing epithelia. Here we showed that the Men1 gene is mainly expressed in the crypt compartment of the proximal small intestine and that its expression was increased during fasting in vivo, both suggesting a role of menin in the control of cell growth. Indeed, specific reduction of menin expression by transfected antisense cDNA in the rat duodenal crypt-like cell line, IEC-17, increased cell proliferation. The latter is correlated to a loss of cell-cycle arrest in G(1) phase by resting cells and an overexpression of cyclin D1 and cyclin-dependent kinase (Cdk)-4. Furthermore, these cells lost the inhibition of proliferation induced by transforming growth factor-beta1, associated with a decrease of transforming growth factor-beta type II receptor expression. As a result of deregulated proliferation, antisense menin transfected IEC-17 cells became tumorigenic as shown in vitro as well as in vivo in immunosuppressed animals. These results indicate that menin contributes to proliferation control in intestinal epithelial cells. The present study reveals an unknown physiological function for menin in intestine that may be important in the regulation of epithelial homeostasis.
Ratineau
Christelle
C
INSERM U45, 69008 Lyon, France.
Bernard
Christine
C
Poncet
Gilles
G
Blanc
Martine
M
Josso
Claire
C
Fontanière
Sandra
S
Calender
Alain
A
Chayvialle
Jean Alain
JA
Zhang
Chang-Xian
CX
Roche
Colette
C
D000362:Agar / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002469:Cell Separation; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D005215:Fasting; D005434:Flow Cytometry; D016193:G1 Phase; D006579:Heterozygote; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D017403:In Situ Hybridization; D007421:Intestine, Small / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C105373:MEN1 protein, human; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D019938:Cyclin D1; D000362:Agar; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C495902:Cdk4 protein, mouse; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II