Interaction of heterogeneous nuclear ribonucleoprotein C1/C2 with a novel cis-regulatory element within p53 mRNA as a response to cytostatic drug treatment

被引：54

作者：

Christian, Kyle J. ^{[1
]}

Lang, Matti A. ^{[1
]}

Raffalli-Mathieu, Francoise ^{[2
]}

机构：

[1] Uppsala Univ, Ctr Biomed, Div Pharmaceut Biochem, S-75123 Uppsala, Sweden

[2] Uppsala Univ, Ctr Biomed, Dept Biochem & Org Chem, S-75123 Uppsala, Sweden

来源：

MOLECULAR PHARMACOLOGY | 2008年 / 73卷 / 05期

关键词：

D O I：

10.1124/mol.107.042507

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

We describe a novel cis-element in the 5' coding region of p53 mRNA and its interaction with heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2. This element is located in a putative hairpin loop structure, within the first 101 nucleotides downstream of the start codon. The binding of hnRNPC1/C2 is strongly enhanced in response to the DNA-damaging drug cisplatin [cis-diamminedichloroplatinum(II)] and the cytostatic transcriptional inhibitor actinomycin D (dactinomycin), both known inducers of apoptosis and p53. Strongly stimulated binding is observed in both nuclear and cytoplasmic compartments, and it is accompanied by a cytoplasmic increase of hnRNPC1/C2. Changes in hnRNPC1/C2 protein levels are not proportional to binding activity, suggesting qualitative changes in hnRNPC1/C2 upon activation. Phosphorylation studies reveal contrasting characteristics of the cytoplasmic and nuclear hnRNPC1/C2 interaction with p53 mRNA. Results from chimeric p53-luciferase reporter constructs suggest that hnRNPC1/C2 regulates p53 expression via this binding site. Our results are consistent with a mechanism in which the interaction of hnRNPC1/C2 with a cis-element within the coding region of the p53 transcript regulates the expression of p53 mRNA before and during apoptosis. In addition, we report that preapoptotic signals induced by transcriptional inhibition trigger the appearance of a truncated, exclusively cytoplasmic 43-kDa variant of p53 before apoptosis.

引用

页码：1558 / 1567

页数：10

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