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First published on February 22, 2008; DOI: 10.1124/mol.107.042507

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Kyle J Christian
Matti A. Lang
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Received for publication October 9, 2007.
Revised February 21, 2008.
Accepted for publication February 21, 2008.

Interaction of hnRNPC1/C2 with a novel cis-regulatory element within p53 mRNA as a response to cytostatic drug treatment

Kyle J Christian 1*, Matti A. Lang 1, Francoise Raffali-Mathieu 2

1 Uppsala University, Pharmaceutical Biosciences 2 Uppsala University, Biochemistry and Organic Chemistry

* Address correspondence to: E-mail: kyle.christian{at}farmbio.uu.se

Abstract

We describe a novel cis-element in the 5' coding region of p53 mRNA and its interaction with hnRNPC1/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 and the cytostatic transcriptional inhibitor actinomycin D, both known inducers of apoptosis and p53. Strongly stimulated binding is observed in both nuclear and cytoplasmic compartments and is accompanied by a cytoplasmic increase of hnRNPC1/C2. Changes in hnRNPC1/C2 protein levels are not proportional to binding activity, thus 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 where 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 pre-apoptotic signals induced by transcriptional inhibition trigger the appearance of a truncated, exclusively cytoplasmic 43 kDa variant of p53 prior to apoptosis.


Key words: Mutagenesis/Chimeric approaches, Regulation of gene expression, Apoptosis, DNA damage and repair, Toxicant-induced gene express, RNA/siRNA, Mechanisms of cell killing/apoptosis, DNA intercalation, Tumor suppressors




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