Lack of CCAAT enhancer binding protein beta (C/EBPbeta) in uterine epithelial cells impairs estrogen-induced DNA replication, induces DNA damage response pathways, and promotes apoptosis.
Female mice lacking the transcription factor C/EBPbeta are infertile and display markedly reduced estrogen (E)-induced proliferation of the uterine epithelial lining during the reproductive cycle. The present study showed that E-stimulated luminal epithelial cells of a C/EBPbeta-null uterus are able to proceed through the G1 phase of the cell cycle before getting arrested in the S phase. This cell cycle arrest was accompanied by markedly reduced levels of expression of E2F3, an E2F family member, and a lack of nuclear localization of cyclin E, a critical regulator of cdk2. An increased nuclear accumulation of p27, an inhibitor of the cyclin E-cdk2 complex, was also observed for the mutant epithelium. Gene expression profiling of C/EBPbeta-null uterine epithelial cells revealed that the blockade of E-induced DNA replication triggers the activation of several well-known components of the DNA damage response pathway, such as ATM, ATR, histone H2AX, checkpoint kinase 1, and tumor suppressor p53. The activation of p53 by ATM/ATR kinase led to increased levels of expression of p21, an inhibitor of G1-S-phase progression, which helps maintain cell cycle arrest. Additionally, p53-dependent mechanisms contributed to an increased apoptosis of replication-defective cells in the C/EBPbeta-null epithelium. C/EBPbeta, therefore, is an essential mediator of E-induced growth and survival of uterine epithelial cells of cycling mice.
Ramathal
Cyril
C
Department of Cell and Developmental Biology, and Center for Research in Reproduction and Infertility, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Bagchi
Indrani C
IC
Bagchi
Milan K
MK
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D037281:Calnexin / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000166:cytology* / Q000187:drug effects
D022782:CCAAT-Enhancer-Binding Protein-beta; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D037281:Calnexin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004958:Estradiol