Browsing by keyword "E2F Transcription Factors"

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    • E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis
      Rogoff, Harry A.; Pickering, Mary Theresa; Debatis, Michelle E.; Jones, Stephen N.; Kowalik, Timothy F. (2002-07-09)
      It has been proposed that the E2F1 transcription factor serves as a link between the Rb/E2F proliferation pathway and the p53 apoptosis pathway by inducing the expression of p19ARF, a protein that regulates p53 stability. We find that although p19ARF contributes to p53 accumulation in response to E2F expression, p19ARF is not required for E2F1-mediated apoptosis. E2F1 can signal p53 phosphorylation in the absence of p19ARF, similar to the observed modifications to p53 in response to DNA damage. These modifications are not observed in the absence of p19ARF following expression of E2F2, an E2F family member that does not induce apoptosis in mouse embryo fibroblasts but can induce p19ARF and p53 protein expression. p53 modification is found to be crucial for E2F1-mediated apoptosis, and this apoptosis is compromised when E2F1 is coexpressed with a p53 mutant lacking many N- and C-terminal phosphorylation sites. Additionally, E2F1-mediated apoptosis is abolished in the presence of caffeine, an inhibitor of phosphatidylinositol 3-kinase-related kinases that phosphorylate p53. These findings suggest that p53 phosphorylation is a key step in E2F1-mediated apoptosis and that this modification can occur in the absence of p19ARF.

    • Gene profiling of cell cycle progression through S-phase reveals sequential expression of genes required for DNA replication and nucleosome assembly
      van der Meijden, Caroline M. J.; Lapointe, David S.; Luong, Mai X.; Peric-Hupkes, Daniel; Cho, Brian C.; Stein, Janet L.; Van Wijnen, Andre J.; Stein, Gary S. (2002-05-31)
      The ordered expression of genes after growth factor stimulation in G(1) supportsthe onset of DNA replication. To characterize regulatory events during S-phase when cell cycle progression has become growth factor independent, we have profiled the expression of over 7,000 human genes using GeneChip DNA microarray analysis. HeLa cells were synchronized at the beginning of S-phase by thymidine/aphidicolin block, and RNA populations were analyzed throughout the S and G(2) phases. Expression of genes involved in DNA replication is maximal during early S-phase, whereas histone mRNAs peak at mid S-phase. Genes related to cell proliferation, including those encoding cyclins, oncoproteins, growth factors, proteins involved in signal transduction, and DNA repair proteins, follow distinct temporal patterns of expression that are functionally linked to initiation of DNA replication and progression through S-phase. The timing of expression for many genes in tumor-derived HeLa cells is highly conserved when compared with normal cells. In contrast, a number of genes show growth phenotype-related expression patterns that may directly reflect loss of stringent growth control in tumor cells. Our data reveal there is a core subset of cell growth-related genes that is fundamental to cycling cells irrespective of cell growth phenotype.

    • Ras stimulation of E2F activity and a consequent E2F regulation of integrin alpha6beta4 promote the invasion of breast carcinoma cells
      Yoon, Sang-oh; Shin, Sejeong; Mercurio, Arthur M. (2006-06-17)
      Active Ras proteins contribute to breast carcinogenesis and progression. Here, we provide evidence that active H-Ras regulates the expression and activity of the E2F family of transcription factors in SUM-159 breast carcinoma cells. In addition, we show by using a DNA-binding mutant of E2F, as well as expression of specific E2Fs that are transcriptionally active, that the active E2Fs1-3 can mediate the H-Ras-dependent invasion of SUM-159 cells. The inhibitory E2Fs4-5, in contrast, do not influence invasion. One mechanism by which the active E2Fs promote H-Ras-dependent invasion seems to be their ability to increase expression of the beta4 integrin subunit, a component of the alpha6beta4 integrin that is known to enhance carcinoma invasion. Specifically, expression of E2Fs1-3 increased beta4 mRNA, protein, and cell surface expression. The active E2Fs were unable to stimulate invasion in cells that expressed a beta4 short hairpin RNA. This effect of the active E2Fs on beta4 expression does not seem to result from E2F-mediated beta4 transcription because the beta4 promoter lacks known E2F binding motifs. In summary, the data reported here indicate a novel mechanism by which H-Ras can promote the invasion of breast carcinoma cells. This mechanism links active H-Ras, transcriptionally active E2F, and the alpha6beta4 integrin in a common pathway that culminates in enhanced alpha6beta4-dependent invasion.

    • Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability
      Imbalzano, Anthony N.; Jones, Stephen N. (2005-04-20)
      SNF5 is a core subunit of the SWI/SNF chromatin-remodeling complex. Mammalian SNF5 is essential for normal cell viability, and loss or mutation of the human SNF gene is the molecular basis for familial malignant rhabdoid tumorigenesis. Previous studies have suggested that SNF5 suppresses cancer by signaling through the p16Ink4a and retinoblastoma tumor suppressors to negatively regulate cell cycle progression from G0/G1 into S phase. A recent paper in Genes and Development (Vries et al., 2005) reports that human SNF5 also signals via the p16INK4a-Rb-E2F pathway to regulate chromosomal stability, suggesting a new function for this chromatin remodeling protein in tumor suppression.