A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation.
Bcr-Abl is a chimeric oncoprotein that is strongly implicated in acute lymphoblastic (ALL) and chronic myelogenous leukemias (CML). This deregulated tyrosine kinase selectively causes hematopoietic disorders resembling human leukemias in animal models and transforms fibroblasts and hematopoietic cells in culture. Bcr-Abl also protects cells from death induced on cytokine deprivation or exposure to DNA damaging agents. In addition, the antiapoptotic function of Bcr-Abl is thought to play a necessary role in hematopoietic transformation and potentially in leukemogenesis. The transcription factor NF-kappaB has been identified recently as an inhibitor of apoptosis and as a potential regulator of cellular transformation. This study shows that expression of Bcr-Abl leads to activation of NF-kappaB-dependent transcription by causing nuclear translocation of NF-kappaB as well as by increasing the transactivation function of the RelA/p65 subunit of NF-kappaB. Importantly, this activation is dependent on the tyrosine kinase activity of Bcr-Abl and partially requires Ras. The ability of Bcr-Abl to protect cytokine-dependent 32D myeloid cells from death induced by cytokine deprivation or DNA damage does not, however, require functional NF-kappaB. However, using a super-repressor form of IkappaBalpha, we show that NF-kappaB is required for Bcr-Abl-mediated tumorigenicity in nude mice and for transformation of primary bone marrow cells. This study implicates NF-kappaB as an important component of Bcr-Abl signaling. NF-kappaB-regulated genes, therefore, likely play a role in transformation by Bcr-Abl and thus in Bcr-Abl-associated human leukemias.
Reuther
J Y
JY
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 USA.
Reuther
G W
GW
Cortez
D
D
Pendergast
A M
AM
Baldwin
A S
AS
D000818:Animals; D017209:Apoptosis; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D016044:Fusion Proteins, bcr-abl