Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation
| Autor: | Diana G. Salerno, Chung H. Kok, Ian D. Lewis, Richard J D'Andrea, Michelle Perugini, Anna L. Brown, Sonya M. Diakiw, Thomas J. Gonda, C. R. Wilkinson, S M Young |
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| Přispěvatelé: | Perugini, M, Kok, CH, Brown, AL, Wilkinson, CR, Salerno, DG, Young, SM, Lewis, ID, Gonda, TJ, D'Andrea, RJ |
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Cell Survival Cellular differentiation Alpha (ethology) Down-Regulation Cell Cycle Proteins Biology Cell Line Mice AML Downregulation and upregulation gadd45a hemic and lymphatic diseases Animals RNA Messenger Cell Proliferation Gene knockdown Mitogen-Activated Protein Kinase 3 GM-CSF Receptor Nuclear Proteins Cell Differentiation Hematology FLT3-ITD mutation body regions Leukemia Myeloid Acute Oncology fms-Like Tyrosine Kinase 3 Cell culture Receptors Granulocyte-Macrophage Colony-Stimulating Factor Trk receptor Mutation Cancer research FLT3 mutation GADD45A |
| Zdroj: | Leukemia. 23(4) |
| ISSN: | 1476-5551 |
| Popis: | The tumor suppressor Gadd45alpha was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45alpha as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD(+) AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45alpha mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD(+) cell line MV4;11. Knockdown of Gadd45alpha with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45alpha in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45alpha overexpression in FLT3-ITD(+) AML cell lines also resulted in reduced growth associated with increased apoptosis and G(1)/S cell cycle arrest. Overexpression of Gadd45alpha in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45alpha downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45alpha by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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