HIFs Enhance the Transcriptional Activation and Splicing of Adrenomedullin
| Autor: | Liyi Wang, Matthew R. Pawlus, Johnny Sena, Cheng-Jun Hu |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Transcriptional Activation
Gene isoform Cancer Research RNA Splicing Intron Biology Hypoxia-Inducible Factor 1 alpha Subunit Transfection Article Cell Hypoxia Adrenomedullin Oncology Transcription (biology) Gene Knockdown Techniques Gene expression RNA splicing Human Umbilical Vein Endothelial Cells Cancer research Humans Molecular Biology Transcription factor Gene |
| Zdroj: | Molecular Cancer Research. 12:728-741 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Adrenomedullin (ADM) is important for tumor angiogenesis, tumor cell growth, and survival. Under normoxic conditions, the ADM gene was found to produce two alternative transcripts, a fully spliced transcript that produces AM and PAMP peptides and intron-3–retaining transcript that produces a less functionally significant PAMP peptide only. ADM is a well-established hypoxia inducible gene; however, it is not clear which ADM isoform is induced by hypoxia. In this study, it was determined that various cancer and normal cells express two predominant types of ADM transcripts, a AM/PAMP peptide producing full-length transcript in which all introns are removed, and a nonprotein producing I1-3 transcript in which all introns are retained. Interestingly, hypoxia preferentially induced the full-length isoform. Moreover, hypoxia-inducible factors (HIF), but not hypoxia per se, are necessary and sufficient to increase splicing of ADM pre-mRNA. ADM splicing reporters confirmed that transcriptional activation by HIF or other transcription factors is sufficient to enhance splicing. However, HIFs are more potent in enhancing ADM pre-mRNA splicing than other transcriptional activators. Thus, ADM intron retention is not a consequence of abnormal splicing, but is an important mechanism to regulate ADM expression. These results demonstrate a novel function of HIFs in regulating ADM expression by enhancing its pre-mRNA splicing. Importantly, using endogenous and cloned ADM gene, further evidence is provided for the coupling of transcription and RNA splicing. Implications: Here, a novel function of HIFs in regulating ADM gene expression is identified by enhancing ADM pre-mRNA splicing. Mol Cancer Res; 12(5); 728–41. ©2014 AACR. |
| Databáze: | OpenAIRE |
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