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hnRNP C1/C2 represses the expression of human p53 via two distinct mechanisms.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-97205OAI: oai:DiVA.org:uu-97205DiVA: diva2:172033
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2010-01-13Bibliographically 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

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