Title | Enhanced proliferative potential of hematopoietic cells expressing degradation-resistant c-Myb mutants |
---|---|
Publication Type | Articolo su Rivista peer-reviewed |
Year of Publication | 2005 |
Authors | Corradini, F., Cesi Vincenzo, Bartella V., Pani E., Bussolari R., Candini O., and Calabretta B. |
Journal | Journal of Biological Chemistry |
Volume | 280 |
Pagination | 30254-30262 |
ISSN | 00219258 |
Keywords | 1-Phosphatidylinositol 3-Kinase, Alanine, amino acid substitution, animal cell, Animals, Apoptosis, article, BCR ABL protein, Blotting, bone marrow cell, cell assay, Cell cycle, cell differentiation, Cell Line, cell proliferation, cell strain, cell strain k 562, Cell Survival, Cells, colony formation, controlled study, cytokine, Dominant, enzyme activation, enzyme activity, Enzyme inhibition, Enzymes, gene expression regulation, Genes, Genetic, glycogen synthase kinase 3beta, half life time, hematologic malignancy, Hematological malignancies, hematopoietic cell, Hematopoietic cells, Hematopoietic Stem Cells, human, human cell, Humans, Inbred C57BL, Interleukin-3, K562 Cells, leucine, leucine zipper protein, leukemia cell, lithium chloride, lysine, Messenger, Mice, mouse, Mutagenesis, mutant protein, mutation, nonhuman, Northern, oncogene c myb, phosphatidylinositol 3 kinase, phosphatidylinositol 3 kinase inhibitor, Piperazines, Plasmids, priority journal, proteasome inhibitor, protein c Myb, protein domain, protein expression, protein function, protein kinase B, protein kinase inhibitor, protein stability, Protein Structure, Proto-Oncogene Proteins c-myb, Pyrimidines, regulatory mechanism, Retroviridae, RNA, signal transduction, Small Interfering, Tertiary, Time Factors, Transcription, transcription factor, Transfection, Tumor, Tumors, ubiquitin, Western, wild type |
Abstract | 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/ GSKIIIβ 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 GSKIIIβ. Moreover, inhibition of GSKIIIβ by LiCl enhanced c-Myb expression in parental 32Dc13 cells. Compared with wild type c-Myb, three mutants (Δ(358-452), Δ(389-418), and L389A/L396A c-Myb) of the leucine zipper domain had increased stability. However, only expression of Δ(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, Δ(389-418) carrying four lysine-to-alanine substitutions (Δ(389-418) K387A/K428A/K442A/K445A) was as stable as Δ(358-452) c-Myb. Compared with full-length c-Myb, constitutive expression of Δ(358-452) and Δ(389-418) c-Myb in Lin-Sca-1+ mouse marrow cells increased cytokine-dependent primary and secondary colony formation. In K562 cells, expression of Δ(358-452), Γ(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. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. |
Notes | cited By 25 |
URL | https://www.scopus.com/inward/record.uri?eid=2-s2.0-24044548990&doi=10.1074%2fjbc.M504703200&partnerID=40&md5=838410aaa561f2b2b81caecfee72e87a |
DOI | 10.1074/jbc.M504703200 |
Citation Key | Corradini200530254 |