非典型E2F转录因子对细胞周期的调控及其功能

E2F家族转录因子是细胞周期调控网络中的重要环节之一,对细胞的增殖、分化和凋亡进行调节,并参与多种生理和病理过程。近年来,关于哺乳动物中E2F转录因子的生物学作用研究取得了很大进展,并鉴定出两个非典型的E2F家族成员：E2F7和E2F8。与典型的E2F转录因子相比,非典型E2F蛋白结构中含有两个相同的DNA结合域,对靶基因转录的调控不依赖于二聚化蛋白。非典型E2F蛋白进入细胞核后,通过与经典的E2F靶基因启动子结合,发挥转录抑制作用并调节细胞周期的进程,从而对细胞的大小、多倍化、增殖、分化和凋亡进行调控。随着基因敲除模型的建立和完善,使得进一步研究非典型E2F转录因子在不同组织或器官中的生物学作用成为可能。非典型E2F在胚胎发育、血管发生及造血系统中均发挥重要作用。另外,肿瘤细胞中典型E2F和非典型E2F的表达比例发生改变,说明非典型E2F成员还参与肿瘤的发生发展。该文综述了近年来关于非典型E2F转录因子的表达、调节及其生理病理作用的研究进展。     

4-Hydroxynonenal affects pRb/E2F pathway in HL-60 human leukemic cells

4-Hydroxynonenal (HNE), a highly reactive product of lipid peroxidation, has an antiproliferative effect in several tumor cell lines and provokes alteration of cell cycle progression in HL-60 cells. HNE down-regulates c-myc expression in K562, HL-60, and MEL cells. This prompted us to study the cascade of phenomena that, starting from the CKIs expression and the phosphorylation of pRb, arrives at the E2F binding to consensus sequence in the P2 promoter of the c-myc gene. Treatment of HL-60 cells with HNE (1 microM) causes a p53-independent increase of p21(WAF1/CIP1) expression, pRb dephosphorylation, a decrease of low molecular weight E2F complexes and an increase of high molecular weight E2F complexes bound to P2 c-myc promoter. E2F4 expression is reduced by HNE treatment as well as the amount of pRb/E2F4 complexes, whereas the amount of pRb/E2F1 complexes is increased. In conclusion, HNE can affect the pRb/E2F pathway by modifying the expression of several genes involved in the control of cell proliferation.     

DNA-damage response control of E2F7 and E2F8

Here, we report that the two recently identified E2F subunits, E2F7 and E2F8, are induced in cells treated with DNA-damaging agents where they have an important role in dictating the outcome of the DNA-damage response. The DNA-damage-dependent induction coincides with the binding of E2F7 and E2F8 to the promoters of certain E2F-responsive genes, most notably that of the E2F1 gene, in which E2F7 and E2F8 coexist in a DNA-binding complex. As a consequence, E2F7 and E2F8 repress E2F target genes, such as E2F1, and reducing the level of each subunit results in an increase in E2F1 expression and activity. Importantly, depletion of either E2F7 or E2F8 prevents the cell-cycle effects that occur in response to DNA damage. Thus, E2F7 and E2F8 act upstream of E2F1, and influence the ability of cells to undergo a DNA-damage response. E2F7 and E2F8, therefore, underpin the DNA-damage response.     

Anti-oncogenic microRNA-203 induces senescence by targeting E2F3 protein in human melanoma cells

MicroRNAs regulate gene expression by repressing translation or directing sequence-specific degradation of their complementary mRNA. We recently reported that miR-203 is down-regulated, and its exogenous expression inhibits cell growth in canine oral malignant melanoma tissue specimens as well as in canine and human malignant melanoma cells. A microRNA target database predicted E2F3 and ZBP-89 as putative targets of microRNA-203 (miR-203). The expression levels of E2F3a, E2F3b, and ZBP-89 were markedly up-regulated in human malignant melanoma Mewo cells compared with those in human epidermal melanocytes. miR-203 significantly suppressed the luciferase activity of reporter plasmids containing the 3'-UTR sequence of either E2F3 or ZBP-89 complementary to miR-203. The ectopic expression of miR-203 in melanoma cells reduced the levels of E2F3a, E2F3b, and ZBP-89 protein expression. At the same time, miR-203 induced cell cycle arrest and senescence phenotypes, such as elevated expression of hypophosphorylated retinoblastoma and other markers for senescence. Silencing of E2F3, but not of ZBP-89, inhibited cell growth and induced cell cycle arrest and senescence. These results demonstrate a novel role for miR-203 as a tumor suppressor acting by inducing senescence in melanoma cells.