Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues.
The POU-domain transcription factor Oct-4 is normally expressed in pluripotent cells of the mammalian embryo. In addition, germ-cell tumors and a few somatic tumors show detectable expression of Oct-4. While Oct-4's role during preimplantation development is to maintain embryonic cells in a pluripotent state, little is known about its potential oncogenic properties. Here we investigate the effect of ectopic Oct-4 expression on somatic tissues of adult mice using a doxycycline-dependent expression system. Activation of Oct-4 results in dysplastic growths in epithelial tissues that are dependent on continuous Oct-4 expression. Dysplastic lesions show an expansion of progenitor cells and increased beta-catenin transcriptional activity. In the intestine, Oct-4 expression causes dysplasia by inhibiting cellular differentiation in a manner similar to that in embryonic cells. These data show that certain adult progenitors remain competent to interpret key embryonic signals and support the notion that progenitor cells are a driving force in tumorigenesis.
Hochedlinger
Konrad
K
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Yamada
Yasuhiro
Y
Beard
Caroline
C
Jaenisch
Rudolf
R
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004318:Doxycycline / Q000008:administration & dosage / Q000633:toxicity; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D050814:Octamer Transcription Factor-3; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D004318:Doxycycline