| Autor: |
Perugini, M., Kok, C. H., Brown, A. L., Wilkinson, C. R., Salerno, D. G., Young, S. M., Diakiw, S. M., Lewis, I. D., Gonda, T. J., D'Andrea, R. J. |
| Předmět: |
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| Zdroj: |
Leukemia (08876924); Apr2009, Vol. 23 Issue 4, p729-738, 10p, 1 Chart, 6 Graphs |
| Abstrakt: |
The tumor suppressor Gadd45α was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45α 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 Gadd45α mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD+ cell line MV4;11. Knockdown of Gadd45α with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45α in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45α overexpression in FLT3-ITD+ AML cell lines also resulted in reduced growth associated with increased apoptosis and G1/S cell cycle arrest. Overexpression of Gadd45α in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45α downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45α by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.Leukemia (2009) 23, 729–738; doi:10.1038/leu.2008.349; published online 8 January 2009 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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