uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Interaction of Heterogeneous Nuclear Ribonucleoprotein C1/C2 with a Novel cis-Regulatory Element within p53 mRNA as a Response to Cytostatic Drug Treatment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2008 (English)In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 73, no 5, 1558-1567 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 73, no 5, 1558-1567 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97204DOI: 10.1124/mol.107.042507OAI: oai:DiVA.org:uu-97204DiVA: diva2:172032
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2013-05-16Bibliographically approved
In thesis
1. The role of hnRNP A1 and hnRNP C1/C2 in the regulation of the stress responsive genes Cyp2a5/2A6 and p53.
Open this publication in new window or tab >>The role of hnRNP A1 and hnRNP C1/C2 in the regulation of the stress responsive genes Cyp2a5/2A6 and p53.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The family of proteins known as heterogeneous nuclear ribonucleoproteins (hnRNPs) is large and diverse. Often, one and the same hnRNP will perform multiple cellular functions, leading to their description as “multifunctional proteins”. The two hnRNPs known as hnRNP A1 and hnRNP C1/C2 are multifunctional proteins found to affect the transcription, splicing, stability, and translation of specific genes’ mRNA. They are implicated in carcinogenesis, apoptosis, and DNA damage response mechanisms.

The aims of this thesis were to study the hnRNP A1 and hnRNP C1/C2 dependent regulation of two highly stress responsive genes, the tumor suppressor p53 and the cytochrome P450 enzyme Cyp2a5/CYP2A6. We identified hnRNP C1/C2 as a DNA damage induced binding protein towards the coding region of p53 mRNA, and found that while a specific cis binding site appears to have a positive function in p53 expression, interaction of hnRNP C1/C2 with this site represses the expression. The data suggest that two distinct molecular mechanisms exist for the down-regulation of p53 by hnRNP C1/C2. One mechanism, active during transcriptional stress, is dependent upon the aforementioned site, and the other, independent. We discuss how hnRNP C1/C2 dependent repression of p53 may play a role in apoptosis.

The data presented here further suggest that the transcriptional and post-transcriptional processes controlling the expression of the murine Cyp2a5 gene are linked via hnRNP A1, by performing functions in the nucleus as a transcription factor, or in the cytoplasmic compartment as a trans factor bound to the 3’UTR of the mRNA as needed. Our studies of the human ortholog of this gene, CYP2A6, suggest that this gene is regulated post-transcriptionally in a manner similar to that of its murine counterpart, via changes in mRNA stability and interaction of hnRNP A1 with its 3’ UTR.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 90 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 74
Keyword
Molecular biology, hnRNP, Tumor Suppressor Protein p53, CYP2A5, CYP2A6, Apoptosis, hnRNP C Proteins, hnRNP protein A1, Cancer, Molekylärbiologi
Identifiers
urn:nbn:se:uu:diva-8722 (URN)978-91-554-7198-9 (ISBN)
Public defence
2008-05-23, BMC/C2:301, Biomedicinsk Centrum, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2013-05-03Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text
By organisation
Department of Pharmaceutical BiosciencesDepartment of Biochemistry and Organic Chemistry
In the same journal
Molecular Pharmacology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 489 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf