Proceedings of the National Academy of Sciences - PNAS, 2005-12, Vol.102 (50), p.18081-18086
2005
Details
- Autor(en) / Beteiligte
- Titel
- MicroRNAs 221 and 222 Inhibit Normal Erythropoiesis and Erythroleukemic Cell Growth via Kit Receptor Down-Modulation
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2005-12, Vol.102 (50), p.18081-18086
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2005
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression primarily through translational repression. In erythropoietic (E) culture of cord blood CD34+ progenitor cells, the level of mlR 221 and 222 is gradually and sharply down-modulated. Hypothetically, this decline could promote erythropoiesis by unblocking expression of key functional proteins. Indeed, (i) bioinformatic analysis suggested that miR 221 and 222 target the 3' UTR of kit mRNA; (ii) the luciferase assay confirmed that both miRs directly interact with the kit mRNA target site; and (iii) in E culture undergoing exponential cell growth, miR down-modulation is inversely related to increasing kit protein expression, whereas the kit mRNA level is relatively stable. Functional studies show that treatment of CD34+ progenitors with miR 221 and 222, via oligonucleotide transfection or lentiviral vector infection, causes impaired proliferation and accelerated differentiation of E cells, coupled with down-modulation of kit protein: this phenomenon, observed in E culture releasing endogenous kit ligand, is magnified in E culture supplemented with kit ligand. Furthermore, transplantation experiments in NOD-SCID mice reveal that miR 221 and 222 treatment of CD34+ cells impairs their engraftment capacity and stem cell activity. Finally, miR 221 and 222 gene transfer impairs proliferation of the kit+ TF-1 erythroleukemic cell line. Altogether, our studies indicate that the decline of miR 221 and 222 during exponential E growth unblocks kit protein production at mRNA level, thus leading to expansion of early erythroblasts. Furthermore, the results on kit+ erythroleukemic cells suggest a potential role of these miRs in cancer therapy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.0506216102Titel-ID: cdi_proquest_miscellaneous_68895731
- Format
- –
- Schlagworte
- Animals, Antigens, CD34 - metabolism, B lymphocytes, Biological Sciences, Cancer, Cell culture, Cell Differentiation - genetics, Cell growth, Cell lines, Cell Proliferation, Cells, Computational Biology, Cultured cells, Erythropoiesis, Erythropoiesis - genetics, Erythropoiesis - physiology, Fetal Blood - cytology, Gene Expression Profiling, Gene Expression Regulation - genetics, Genetics, Hematopoietic Stem Cells - metabolism, Humans, K562 cells, Luciferases, Messenger RNA, Mice, Mice, Inbred NOD, Mice, SCID, MicroRNAs - genetics, MicroRNAs - metabolism, Oligonucleotides, Proteins, Proto-Oncogene Proteins c-kit - metabolism, Ribonucleic acid, RNA, Stem cells