演者: Nicholas Dyson 博士 (通産省工業技術院の短期招聘研究者として来日)
所属: Associate Professor, Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School
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演題: ショウジョウバエの癌抑制遺伝子による細胞周期制御
The control of cell proliferation by E2F and pRB-family proteins.
要旨:The E2F transcription factor provides an important component of cell cycle control. During G1 to S phase progression the activation of cyclin dependent kinases in G1 leads to the phosphorylation of retinoblastoma family proteins (pRB, p107 and p130), and the activation of the E2F-dependent transcription. E2F-binding sites allow the expression of many genes to be temporally regulated such that gene expression is repressed in quiescent cells and then dramatically induced as cells progress from G0/G1 to S-phase. E2F regulates the expression of a set of genes that encode proteins that are essential for DNA synthesis and that drive cell cycle progression. Its targets include cell cycle regulators such as cyclin E, cyclin A, cdc2, B-myb, N-myc, and E2F-1, and genes whose products are required for DNA synthesis, such as cdc6, orc1, DHFR, thymidine kinase, thymidylate synthase and ribonucleotide reductase subunit M2. E2F-dependent transcription is tightly controlled in normal cells but is deregulated in most, if not all, tumor cells. In a number of experimental systems, events that artificially elevate the level of E2F activity drive cells into S phase.
To complement biochemical studies of E2F function in mammalian cells we and others have isolated Drosophila genes encoding homologs of E2F (dE2F, dE2F2, dDP) and the RB-family proteins (RBF, RBF2). Studies of these show the Drosophila proteins control cell proliferation in vivo in ways that are directly analogous to their mammalian counterparts. Our research has two major goals that exploit the advantages of Drosophila. First, in order to identify the key molecules and pathways that functionally interact with E2F and RBF, we have set up genetic screens for mutations that modify dE2F/dDP- and RBF-dependent phenotypes. Second, we are characterizing the phenotypes of mutant alleles of dE2F, dE2F2, dDP, RBF and RBF2. These mutants have phenotypes that are far more severe than mutations of individual E2F or RB-family members in mice and give insights into the general roles of these families of proteins.
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