p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses.
PPP1R13L gene has been found to be over-expressed in variety of cancers and its expression in p53 wild-type background is sufficient to promote tumor growth in vivo. However, in the non-transformed cells it acts as a tumor suppressor which suggests that the role of PPP1R13L is multifaceted.We have used siRNA ... optimized for inhibition of p53, PPP1R13L, BAX and GADD45 alpha expression and investigated the role of those gene products for PPP1R13L expression and induction in a variety of mouse and human cells with different p53 status. In addition we have applied Western Blot, Q-PCR and proteasome inhibition analysis to further ascertain the link between PPP1R13L induction and p53 status.We show that the pattern and extent of the PPP1R13L expression depend on the presence of active p53. Downregulation of p53 target genes BAX and/or GADD45 alpha led to decreased in PPP1R13L activation after adriamycin and/or etoposide treatments. Treatment of the cells with the proteasome inhibitor MG-132 resulted in the accumulation of both p53 and PPP1R13L proteins.We have provided evidence that endogenous PPP1R13L acts as a negative regulator of p53 function, presumably by direct binding. p53 accumulation and activity after DNA damage is compromised by PPP1R13L expression. We suggest that PPP1R13L and p53 form a negative feedback loop which regulates their amount and activity.The profound modulatory effect of the PPP1R13L protein on the ability of p53 to cause cellular apoptosis has important implications in cancer and presents new therapeutic possibilities.
Mesh Terms:
Animals, Antineoplastic Agents, Binding Sites, Blotting, Western, Cell Cycle Proteins, Cell Line, Tumor, Cells, Cultured, DNA Damage, Doxorubicin, Etoposide, Feedback, Physiological, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Leupeptins, Mice, Mutation, Nuclear Proteins, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, RNA Interference, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transcriptional Activation, Tumor Suppressor Protein p53, bcl-2-Associated X Protein
Animals, Antineoplastic Agents, Binding Sites, Blotting, Western, Cell Cycle Proteins, Cell Line, Tumor, Cells, Cultured, DNA Damage, Doxorubicin, Etoposide, Feedback, Physiological, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Leupeptins, Mice, Mutation, Nuclear Proteins, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, RNA Interference, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transcriptional Activation, Tumor Suppressor Protein p53, bcl-2-Associated X Protein
Biochim. Biophys. Acta
Date: Dec. 01, 2010
PubMed ID: 20840860
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