The c-myb gene encodes a transcription factor required for proliferation, differentiation, and survival of hematopoietic cells. Expression of c-Myb is often increased in hematological malignancies, but the underlying mechanisms are poorly understood. We show here that c-Myb has a longer half-life ( at least 2-fold) in BCR/ABL-expressing than in normal hematopoietic cells. Such enhanced stability was dependent on a phosphatidylinositol 3-kinase ( PI-3K)/Akt/GSKIII beta pathway( s) as indicated by the suppression of c-Myb expression upon treatment with PI-3K inhibitors or co-expression with dominant negative Akt or constitutively active GSKIII beta. Moreover, inhibition of GSKIII beta by LiCl enhanced cMyb expression in parental 32Dcl3 cells. Compared with wild type c-Myb, three mutants ( Delta( 358 - 452), Delta( 389 - 418), and L389A/L396A c-Myb) of the leucine zipper domain had increased stability. However, only expression of Delta( 358 - 452) was not affected by inhibition of the PI-3K/Akt pathway and was not enhanced by a proteasome inhibitor, suggesting that leucine zipper-dependent and - independent mechanisms are involved in the regulation of c-Myb stability. Indeed, Delta( 389 - 418) carrying four lysine-to-alanine substitutions ( Delta( 389 - 418) K387A/K428A/ K442A/K445A) was as stable as Delta( 358 - 452) c-Myb. Compared with full-length c-Myb, constitutive expression of Delta( 358 - 452) and Delta( 389 - 418) c-Myb in Lin-Sca-1(+) mouse marrow cells increased cytokine-dependent primary and secondary colony formation. In K562 cells, expression of Delta( 358 - 452), Delta( 389 - 418), and L389A/L396A c-Myb led to enhanced proliferation after STI571 treatment. Thus, enhanced stability of c-Myb by activation of PI-3K-dependent pathway( s) might contribute to the higher proliferative potential of BCR/ABL-expressing and, perhaps, other leukemic cells.
|Anno di pubblicazione:||2005|
|Titolo:||Enhanced proliferative potential of hematopoietic cells expressing degradation-resistant c-Myb mutants|
|Autori:||Corradini F; Cesi V; Bartella V; Pani E; Bussolari R; Candini O; Calabretta B|
|Appare nelle tipologie:||Articolo su rivista|
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