p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses.
Biochim Biophys Acta
; 1800(12): 1231-40, 2010 Dec.
Article
em En
| MEDLINE
| ID: mdl-20840860
ABSTRACT
BACKGROUND:
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.METHODS:
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.RESULTS:
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.CONCLUSIONS:
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. GENERALSIGNIFICANCE:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Dano ao DNA
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Proteína Supressora de Tumor p53
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Retroalimentação Fisiológica
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Peptídeos e Proteínas de Sinalização Intracelular
Limite:
Animals
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Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Dinamarca