<<In your post #871 you floated up concerns that Barnes et al had on the potential
inadvisability of prolonged disruption of NF-kB owing to concerns over immune
function. How selective is Apanol in targeting a response and do you or others think
these potential secondary effects may be a material stumbling block in a phase III
experience?>>
ncbi.nlm.nih.gov
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Genes Dev 1998 Apr 1;12(7):968-981
A requirement for NF-kappaB activation in
Bcr-Abl-mediated transformation.
Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS Jr
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599 USA.
[Record supplied by publisher]
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.
PMID: 9531535
Free Online Service<<http://www.northernminer.com/free/home.html#Stories>>
Chuca
What possible Damage you ask, This has been up on one of MY TRHEE Top Ten Hot Links since 1 April 1998, see and weep, I think ( JMHO):
techstocks.com
<< 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.>> and <<..shows that expression of
Bcr-Abl leads to activation of NF-kappaB-dependent transcription by causing nuclear translocation of NF-kappaB as well..>> |
