Basic anatomy and tumor biology of the RPS6KA6 gene that encodes the p90 ribosomal S6 kinase-4
| Autor: | Yuan Sun, Min Yang, Sihong Wu, D.J. Liao, Xiangrang Song, Zhe Wang, Xiukun Lin, Shousong Cao |
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| Rok vydání: | 2012 |
| Předmět: |
Protein isoform
Cancer Research Apoptosis Mice SCID Immunoenzyme Techniques Mice Exon 0302 clinical medicine Neoplasms Tumor Cells Cultured Protein Isoforms Cyclin D1 RNA Small Interfering 0303 health sciences Reverse Transcriptase Polymerase Chain Reaction Cell Cycle Exons Cell cycle 3. Good health 030220 oncology & carcinogenesis Azacitidine Female Transcription Initiation Site Gene isoform Antimetabolites Antineoplastic DNA Complementary Blotting Western Molecular Sequence Data Antineoplastic Agents Biology Real-Time Polymerase Chain Reaction Ribosomal Protein S6 Kinases 90-kDa Article Proto-Oncogene Proteins c-myc 03 medical and health sciences Exon trapping Sequence Homology Nucleic Acid Complementary DNA Cell Adhesion Genetics Animals Humans Immunoprecipitation RNA Messenger Molecular Biology Gene Cell Proliferation 030304 developmental biology Base Sequence Alternative splicing Molecular biology Alternative Splicing |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2012.200 |
| Popis: | The RPS6KA6 gene encodes the p90 ribosomal S6 kinase-4 (RSK4) that is still largely uncharacterized. In this study we identified a new RSK4 transcription initiation site and several alternative splice sites with a 5'-RACE approach. The resulting mRNA variants encompass four possible first start codons. The first 15 nucleotides (nt) of exon 22 in mouse and the penultimate exon in both human (exon 21) and mouse (exon 24) RSK4 underwent alternative splicing, although the penultimate exon deleted variant appeared mainly in cell clines, but not in most normal tissues. Demethylation agent 5-azacytidine inhibited the deletion of the penultimate exon, whereas two indolocarbazole-derived inhibitors of cyclin-dependent kinase 4 or 6 induced deletion of the first 39 nt from exon 21 of human RSK4. In all human cancer cell lines studied, the 90-kDa wild-type RSK4 was sparse but, surprisingly, several isoforms at or smaller than 72 kDa were expressed as detected by seven different antibodies. On immunoblots, each of these smaller isoforms often appeared as a duplet or triplet and the levels of these isoforms varied greatly among different cell lines and culture conditions. Cyclin D1 inhibited RSK4 expression and serum starvation enhanced the inhibition, whereas c-Myc and RSK4 inhibited cyclin D1. The effects of RSK4 on cell growth, cell death and chemoresponse depended on the mRNA variant or the protein isoform expressed, on the specificity of the cell lines, as well as on the anchorage-dependent or -independent growth conditions and the in vivo situation. Moreover, we also observed that even a given cDNA might be expressed to multiple proteins; therefore, when using a cDNA, one needs to exclude this possibility before attribution of the biological results from the cDNA to the anticipated protein. Collectively, our results suggest that whether RSK4 is oncogenic or tumor suppressive depends on many factors. Oncogene (2013) 32, 1794-1810; doi: 10.1038/onc.2012.200; published online 21 May 2012 |
| Databáze: | OpenAIRE |
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