Activated pkbakt phosphorylates bad phosphorylated

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Activated PKB/Akt phosphorylates Bad Phosphorylated Bad is sequestered in cytosol by 14-3-3 Without Bad, Bcl-2 binds to Bax and prevents the release of cytochrome c Stops the apoptotic pathway 20
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Senescence Cellular or Replicative Senescence cellular aging process whereby cells permanently exit the cell cycle part of normal aging of a cell induced by DNA damage not same as quiescence, which is a reversible exit from cell cycle Organismal Senescence Aging of entire organism Characterized by the declining ability to respond to stress Increasing homeostatic imbalance 21
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Cellular Senescence of a population of cells is determined by number of population doublings Skin fibroblast Corneal epithelium 22
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Cellular Senescence marked by beta- galactosidase activity Cornea from young and old patients 23
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DNA damage checkpoint in apoptosis and senescence 24
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p53 is a key regulator of DNA damage response p53 is a transcription factor that is ubiquitously expressed Protein level regulated by destruction via Mdm2 ubiquitin ligase Activity also regulated by phosphorylations Turned on by DNA damage sensing proteins 25
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p53 can trigger DNA repair, apoptosis, or cell cycle arrest ATM or ATR kinase detect DNA damage ATM/ATR phosphorylate p53 Active p53 binds promoters of target genes Target genes are involved in DNA repair, cell cycle arrest, and/or apoptosis The strength and duration of p53 activation results in either reversible arrest, senescence, or apoptosis Examples of targets: Cell cycle arrest-p21 Apoptosis-Bid/Egl-1 26
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Cell cycle kinase inhibitor p16 regulates senescence Overexpression of p16 results in cell cycle arrest p16 binds to and inhibits cdk4/cyclinD complex during early G1 Cdk4/cyclinD1 phosphorylate Rb Rb is a transcriptional repressor that inhibits transcription of genes essential for entry into the cell cycle Rb repression is released after cdk/cyclin phosphorylation High levels of p16 therefore lead to less cell cycle progression by maintaining Rb- mediated repression 27
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