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Interaction of heterogeneous nuclear ribonucleoprotein A1 with cytochrome P450 2A6 mRNA: implications for post-transcriptional regulation of the CYP2A6 gene
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2004 (English)In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 65, no 6, 1405-14 p.Article in journal (Refereed) Published
Abstract [en]

The human xenobiotic-metabolizing enzyme cytochrome P450, CYP2A6, catalyzes the bioactivation of a number of carcinogens and drugs and is overexpressed in cases of liver diseases, such as cirrhosis, viral hepatitis, and parasitic infestation, and in certain tumor cells. This suggests that CYP2A6 may be a major liver catalyst in pathological conditions. In the present study, we have addressed molecular mechanisms underlying the regulation of the CYP2A6 gene. We present evidence of several proteins present in human hepatocytes that interact specifically with the 3′-untranslated region (UTR) of CYP2A6 mRNA. Biochemical and immunological evidence show that the RNA-protein complex of highest intensity contains the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 or a closely related protein. Mapping of the hnRNP A1 binding site within CYP2A6 3′-UTR reveals that the smallest portion of RNA supporting significant binding consists of 111 central nucleotides of the 3′-UTR. Our studies also indicate that hnRNPA1 from HepG2 cancer cells exhibits modified binding characteristics to the CYP2A6 3′-UTR compared with primary hepatocytes. We found that the level of CYP2A6 mRNA remains high in conditions of impaired transcription in primary human hepatocytes, showing that CYP2A6 expression can be affected post-transcriptionally in conditions of cellular stress. Our results indicate that the post-transcriptional regulation involves interaction of the hnRNP A1 protein with CYP2A6 mRNA. The present data suggest that hnRNPA1 is a critical regulator of expression of the human CYP2A6 gene and support the notion that this P450 isoform may be of particular significance in stressed human liver cells.

Place, publisher, year, edition, pages
2004. Vol. 65, no 6, 1405-14 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97203DOI: 10.1124/mol.65.6.1405OAI: oai:DiVA.org:uu-97203DiVA: diva2:172031
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2013-05-03Bibliographically 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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