李利民-细胞损伤-2010-2.ppt

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Reprogramming With Four Transcription Factors A Revolution in Pathology ? Reverse Development Biology ? PNAS, August 31, 2009 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * iPS cells Reprogrammed Adult Cells Treat Sickle-cell Anemia In Mice Rudolf Jaenisch MIT Mature B Cells Reprogrammed To Stem-cell-like State Rudolf Jaenisch MIT Rudolf Jaenisch MIT New Technique Produces Genetically Identical Stem Cells Genes Involved in Stem Cell Differentiation * A Revolution in Pathology ? * * * * The origins of cell cycle checkpoints -Ted Weinert * * Damage checkpoint pathways Control telomere length Induce of cell death by apoptosis Activate DNA repair pathways Activate different transcriptional programms Control the movement of DNA repair proteins to sites of DNA damage Control cell-cycle arrest ATM (ataxia telangiectasia) loss of motor control owing to Purkinje cell loss, masked faces; oculomotor apraxia Immune deficiencies: High frequencies of cancer: （1 in 40,000-300,000 live births） Ataxia: Telangectasias: Dilated small blood vessels; Skin Ocular; Onset 4 to 6 years Recurrent respiratory infections; T-cell function is reduced 14q+ leukemia (T-CLL) B-cell lymphoma ATM phenotype is complex; not only cancer Physiological importance of checkpoint pathways * * DNA-dependent protein kinase (DNA-PK) DNA-PK DS break repair is a major component of the non-homologous end-joining machinery (NHEJ) including V(D)J recombination and immunoglobulin class switching The DNA-PK complex = DNA binding proteins (Ku70 and Ku80) + catalytic subunit (DNA-PKcs) DNA-PKs is found only in vertebrates DNA-PKs defines a subgroup of the PI 3-kinase family After binding to DS breaks DNA-PK phosphorylates DNA-binding proteins Kevin Spring et al., Nature genetics 2002 Radiosensitivety of ATM +/- and ATM-/- cells HUMAN M