E2F3
Transcription factor E2F3 (E2F-3) [KIAA0075]
Publications[править]
Degeneration of the thymic epithelium is believed to be the primary cause of age-associated thymic involution. In order to investigate the molecular events during the early phase of thymic involution, RNA-seq was performed to gain the transcriptional profiles of medullary thymic epithelial cells (mTEC) from mice of 2, 6 and 10 weeks of age. We confirmed and extended the previous observation of declined expression of cell cycle-related genes and diminished E2F3 activity during thymic involution, showing that it occurred as early as 2-6 weeks after birth. Moreover, we demonstrated that mTEC aging was coupled with augmented expression of inflammatory chemokines and cytokines, reminiscent of the senescence-associated secretory phenotype. Impaired cell cycling and proinflammatoty response therefore represent two predominant transcriptional signatures during the very early phase of thymic involution. Taken together, the present study provides not only complimentary information about, but also new insight into the molecular mechanisms underlying age-related degeneration of thymic epithelial cells.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cytokines
- Epithelial Cells
- Female
- Gene Expression Profiling
- Inflammation
- Mice
- Mice, Inbred C57BL
- Thymus Gland
- Transcription, Genetic
- Transcriptome
Keywords
- Cell cycle
- Inflammation
- RNA-seq
- Senescence-associated secretory phenotype (SASP)
- Thymic involution
- mTEC
Idiopathic pulmonary fibrosis is a well-known age-related disease. However, much less recognized has been the aging associated pathogenesis of this disorder. As we and others previously showed that dysregulation of micro-RNAs (miRNAs) was an important mechanism involved in pulmonary fibrosis, the role of these molecules in this pathology in the aged population has not been investigated (Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lü J. [i]Am J Respir Cell Mol Biol[/i] 45: 287-294, 2011; Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E. [i]J Exp Med[/i] 207: 1589-1597, 2010; Pandit KV, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A, Gibson KF, Konishi K, Yousem SA, Singh M, Handley D, Richards T, Selman M, Watkins SC, Pardo A, Ben-Yehudah A, Bouros D, Eickelberg O, Ray P, Benos PV, Kaminski N. [i]Am J Respir Crit Care Med[/i] 182: 220-229, 2010). In this study, by using a lung fibrosis model established in old mice, we found that ablation of miR-34a protected aged animals from developing experimental lung fibrosis. miR-34a was upregulated in lung epithelial cells, but not in lung fibroblasts of aged mice, and miR-34a expression was further increased in epithelial cells of the fibrotic lungs of these old animals. We found that miR-34a induced dysfunctions in alveolar epithelial cells (AECs), as evidenced by increased cellular senescence and apoptosis and mitochondrial aberrations. More importantly, these abnormalities were attenuated in AECs of the fibrotic lungs of aged miR-34a-/- mice. We found that miR-34a targeted Sirt1, a master anti-aging regulator, and two key cell cycle modulators, E2F3 and cyclin E2, in lung epithelial cells, and the repression of these targets was relieved in miR-34a-deficient AECs. In summary, our data suggest that elevated AEC miR-34a plays a critical role in the pathogenesis of pulmonary fibrosis in the aged population. Our study also indicates miR-34a to be a more precise miRNA target for treating this disease that overwhelmingly affects people of advanced age.
MeSH Terms
- Aging
- Alveolar Epithelial Cells
- Animals
- Apoptosis
- Bleomycin
- Cell Line
- Cell Proliferation
- Cellular Senescence
- Fibroblasts
- Humans
- Idiopathic Pulmonary Fibrosis
- Mice
- MicroRNAs
- Mitochondria
- Phenotype
- Up-Regulation
Keywords
- aging
- alveolar epithelial cell
- apoptosis
- lung fibrosis
- micro-RNA
- senescence
Age-associated thymic involution results in diminished T cell output and function in aged individuals. However, molecular mediators contributing to the decline in thymic function during early thymic involution remain largely unknown. Here, we present transcriptional profiling of purified thymic stromal subsets from mice 1, 3, and 6 months of age spanning early thymic involution. The data implicate unanticipated biological functions for a subset of thymic epithelial cells. The predominant transcriptional signature of early thymic involution is decreased expression of cell-cycle-associated genes and E2F3 transcriptional targets in thymic epithelial subsets. Also, expression of proinflammatory genes increases with age in thymic dendritic cells. Many genes previously implicated in late involution are already deregulated by 3-6 months of age. We provide these thymic stromal data sets, along with thymocyte data sets, in a readily searchable web-based platform, as a resource for investigations into thymocyte:stromal interactions and mechanisms of thymic involution.
MeSH Terms
- Aging
- Animals
- Humans
- Mice
- Stromal Cells
- Thymus Gland
- Transcription, Genetic
MicroRNA-449a (miR-449a) was significantly downregulated in 156 lung cancer tissues (p<0.001). We found that the low expression of miR-449a was highly correlated with cancer recurrence and survival of lung cancer patients. The transient introduction of miR-449a caused cell cycle arrest and cell senescence in A549 and 95D cells. Further studies revealed that E2F3 was a direct target of miR-449a in lung cancer cells. miR-449a also suppressed tumor formation in vivo in nude mice. These results suggest that miR-449a plays an important role in lung cancer tumorigenesis and that miR-449a might predict cancer recurrence and survival of lung cancer patients.
MeSH Terms
- Animals
- Carcinogenesis
- Cell Cycle Checkpoints
- Cell Growth Processes
- Cell Line, Tumor
- Cellular Senescence
- E2F3 Transcription Factor
- Female
- Genes, Tumor Suppressor
- Humans
- Lung Neoplasms
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs
- Middle Aged
- RNA, Small Interfering
- Transfection
Keywords
- E2F3
- Lung cancer
- Senescence
- Survival
- miR-449a
Previous studies showed that several miRNAs can regulate pathways involved in UVB-induced premature senescence and response to ultraviolet irradiation. It has also been reported that miR-34c-5p may be involved in senescence-related mechanisms. We propose that miR-34c-5p may play a crucial role in senescence of normal human primary dermal fibroblasts. Here, we explored the roles of miR-34c-5p in UVB-induced premature senescence on dermal fibroblasts. MiR-34c-5p expression was increased in dermal fibroblasts after repeated subcytotoxic UVB treatments. Underexpression of miR-34c-5p in dermal fibroblasts led to a marked delay of many senescent phenotypes induced by repeated UVB treatments. Furthermore, underexpression of miR-34c-5p in dermal fibroblasts can antagonize the alteration of G1-arrested fibroblasts. Moreover, E2F3, which can inactivate p53 pathway and play a role in cell cycle progression, is a down-stream target of miR-34c-5p. Forced down-expression of miR-34c-5p decreased the expression of UVB-SIPS induced P21 and P53 at both mRNA and protein levels. Our data demonstrated that down-regulation of miR-34c-5p can protect human primary dermal fibroblasts from UVB-induced premature senescence via regulations of some senescence-related molecules.
MeSH Terms
- Cells, Cultured
- Cellular Senescence
- Child
- Down-Regulation
- E2F3 Transcription Factor
- Fibroblasts
- Humans
- Male
- MicroRNAs
- Skin
- Tumor Suppressor Protein p53
- Ultraviolet Rays
- p21-Activated Kinases
Keywords
- UVB
- human skin fibroblasts.
- miR-34c-5p
- premature senescence
The retinoblastoma gene, RB1, is one of the most frequently mutated genes in human cancer. Rb heterozygous mice develop pituitary tumors with 100% incidence, and the E2F transcription factors are required for this. To assess whether deregulated E2F activity is sufficient to induce pituitary tumors, we generated transgenic mice expressing an inducible E2F3 protein in the intermediate lobe of the pituitary gland. We found that short-term deregulation of E2F activity, similar to the earliest stages of Rb loss, is able to induce abnormal proliferation of otherwise quiescent melanotrophs. However, while long-term exposure to deregulated E2F activity results in hyperplasia of the intermediate lobe, it did not lead to tumor formation. In fact, melanotrophs become insensitive to sustained E2F stimulation and enter an irreversible senescence-like state. Thus, although deregulated E2F activity results in hyperproliferation, it is not sufficient to mimic loss of Rb, sustain proliferation of melanotrophs, and ultimately induce pituitary tumors. Similarly, we found that primary cells in tissue culture become insensitive to sustained E2F3 activation and undergo premature senescence in a pRB-, p16Ink4a-, and p19Arf-dependent manner. Thus, we conclude that deregulated E2F activity is not sufficient to fully mimic loss of Rb due to the engagement of a senescence response.
MeSH Terms
- Aging
- Animals
- Cell Cycle Proteins
- Cell Proliferation
- Cells, Cultured
- DNA-Binding Proteins
- E2F Transcription Factors
- E2F3 Transcription Factor
- Hyperplasia
- Mice
- Mice, Transgenic
- Pituitary Gland
- Recombinant Proteins
- Transcription Factors
- Transcription, Genetic
The E2F transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor. We have previously shown that E2F3 plays a critical role in mediating the mitogen-induced activation of E2F-responsive genes and contributes to both the inappropriate proliferation and the p53-dependent apoptosis that arise in pRB-deficient embryos. Here we show that E2F3 also has a significant effect on the phenotype of tumor-prone Rb( /-) mice. The absence of E2F3 results in a significant expansion in the life spans of these animals that correlates with a dramatic alteration in the tumor spectrum. E2F3 loss suppresses the development of the pituitary tumors that normally account for the death of Rb( /-) mice. However, it also promotes the development of medullary thyroid carcinomas yielding metastases at a high frequency. This increased aggressiveness does not seem to result from any change in p53 levels or activity in these tumors. We show that, instead, E2F3 loss leads to an increase in the rate of tumor initiation. Finally, analysis of Rb( /-); E2f3( /-) mice shows that this tumor-suppressive function of E2F3 is dose dependent.
MeSH Terms
- Animals
- Animals, Newborn
- Carcinoma, Medullary
- E2F3 Transcription Factor
- Female
- Fetal Viability
- Gene Dosage
- Heterozygote
- Longevity
- Male
- Mice
- Mice, Mutant Strains
- Mutation
- Neoplasm Metastasis
- Phenotype
- Pituitary Neoplasms
- Retinoblastoma Protein
- Thyroid Neoplasms
- Transcription Factors
- Tumor Suppressor Protein p53
The E2F1, -2, and -3 transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor that drive expression of proliferation-associated genes. Here we use mutant mouse strains to investigate E2F3's role in vivo. We show that E2F3 is essential for embryonic viability in the pure 129/Sv background but the presence of C57BL/6 alleles yields some adult survivors. Although growth retarded, surviving E2f3(-/-) animals are initially healthy. However, they die prematurely, exhibiting no obvious tumor phenotype but with the typical signs of congestive heart failure. The defects are completely distinct from those arising in E2f1 mutant mice (S. J. Field et al., Cell 85:549-561; 1996; L. Yamasaki et al., Cell 85:537-548, 1996), supporting the prevailing view that these E2Fs must have some unique biological functions in vivo. To test this model, we examined the phenotypes of E2f1 E2f3 compound mutant mice. Almost all of the developmental and age-related defects arising in the individual E2f1 or E2f3 mice were exacerbated by the mutation of the other E2f. Thus, E2F1 and E2F3 appear to play critical, overlapping roles in the development and maintenance of a variety of tissues. Importantly, this study did identify one major difference in the properties of E2F1 and E2F3: either alone or in combination with E2F1 loss, E2f3 mutation did not increase the incidence of tumor formation. These data strongly suggest that tumor suppression is a specific property of E2F1 and not E2F3.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Cell Cycle Proteins
- DNA-Binding Proteins
- E2F Transcription Factors
- E2F1 Transcription Factor
- E2F3 Transcription Factor
- Embryonic and Fetal Development
- Female
- Heart Failure
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Mutant Strains
- Models, Cardiovascular
- Neoplasms, Experimental
- Phenotype
- Transcription Factors