Shore%20454Ahandouts%202011

Shore%20454Ahandouts%202011 - and tumour cells. In this...

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Ced-3 Egl-1 Ced-9 Ced-4 Normal Cell Pre-cancer Cell Cancer Cell Dead Cell Oncogene Bcl-2 p53 mut Wt p53 Therapeutic Bax,Bak Color = C elegans b/w = mammals BH3 Bcl-2 Apaf-1 Caspase 1
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ABT Bcl-X L Mcl-1 GXP ABT Mcl-1 7
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In normal cells, stress signals lead to the inhibition of MDM2 — one of the main regulators of p53 stability and activity — allowing activation of the tumour-suppressor functions of p53. The ability to induce a p53 response is lost in virtually all cancer cells: by defects in the pathways that prevent downregulation of p53 by MDM2 (for example, by loss of ARF or CHK2 ); by mutational inactivation of p53 itself; or by disruption of the cell-growth- inhibition pathways that mediate the p53 response (for example, by loss of components of the apoptotic cascade, such as caspase-9 or apoptotic protease activating factor 1 ( APAF1 )). 10
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The choice of response to p53 activation is determined, in part, by differential regulation of p53 activity in normal
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Unformatted text preview: and tumour cells. In this model, activation of p53 in normal cells leads to the selective expression of cell-cycle-arrest target genes (such as CDKN1A , which encodes WAF1), resulting in a reversible or permanent inhibition of cell proliferation. In tumour cells, phosphorylation of p53 at Ser46 (through activation of kinases, expression of co-activators such as p53DINP1 or repression of phosphatases such as WIP1) and/or functional interaction with apoptotic cofactors (such as ASPP, JMY and p63/p73) allows for the activation of apoptotic target genes. These cofactors can bind p53 (directly or indirectly) as shown for ASPP and JMY or — as shown for p63 and p73 — assist p53 DNA binding by directly interacting with p53-responsive promoters. Although not proven, it is possible that phosphorylation alters the conformation of p53 to either enhance the interaction with apoptotic cofactors, or allow binding to apoptotic target promoters. 15...
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This note was uploaded on 10/21/2011 for the course BIOC 450 and 45 taught by Professor Various during the Fall '11 term at McGill.

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Shore%20454Ahandouts%202011 - and tumour cells. In this...

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