Conditional E2F1 activation in transgenic mice causes testicular atrophy and dysplasia mimicking human CIS.
E2F1 is a crucial downstream effector of the retinoblastoma protein (pRB) pathway. To address the consequences of short-term increase in E2F1 activity in adult tissues, we generated transgenic mice expressing the human E2F1 protein fused to the oestrogen receptor (ER) ligand-binding domain. The expression of the ER-E2F1 fusion protein, which is inactive in the absence of 4-hydroxy tamoxifen (OHT), was targeted to the testes. We show that short-term activation of E2F1 results in activation of E2F target genes and apoptosis of germ cells. Consistent with our previously published results, the apoptotic response was independent of p53. Persistent E2F1 activation for 3 weeks led to massive apoptosis and severe testicular atrophy with seminiferous tubules containing only Sertoli cells and clusters of undifferentiated spermatogonia. The latter showed high expression of ER-E2F1 and excessive mitotic activity, including atypical mitoses. In addition, gonocyte-like dysplastic germ cells, resembling carcinoma in situ (CIS) cells in humans, appeared. Our results show that a relatively short period of deregulated E2F1 activity in testicles can induce premalignant changes. Moreover, we demonstrate the feasibility of tissue-specific expression of conditional ER-E2F1 in transgenic mice.
Agger
Karl
K
Biotech Research & Innovation Centre, 2100 Copenhagen, Denmark.
Santoni-Rugiu
Eric
E
Holmberg
Christian
C
Karlström
Olle
O
Helin
Kristian
K
D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D001483:Base Sequence; D002278:Carcinoma in Situ / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013094:Spermatozoa / Q000166:cytology; D013736:Testicular Neoplasms / Q000503:physiopathology; D013737:Testis / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D011960:Receptors, Estrogen; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53