MECHANISM OF ACTION OF GM-CSF

Project: Research project

Description

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a very
important agent for the treatment of neutropenia induced by chemotherapy
and AIDS and for the treatment of hematopoietic diseases e.g. aplastic
anemia. GM-CSF may also play a role in stimulating the growth of
hematopoietic tumors e.g. juvenile chronic myelogenous leukemia. Although
this agent is important for the treatment of human disease and possibly
plays a causative role in the growth of some neoplasms, little is known
about the biochemical mechanism of action of this agent. It is goal of
this project to understand how GM-CSF binding to its receptor leads to the
induction of genes associated with cell growth and differentiation. Preliminary results from our laboratory have demonstrated important facts
about the GM-CSF receptor, the mechanism of signal transduction by GM-CSF,
and the genes activated soon after GM-CSF binds to its receptor. We find
that two mRNAs encode the alpha subunit of GM-CSF receptor. One of these
has a single peptide but no transmembrane domain suggesting that it is
secreted. We find that binding of GM-CSF to its receptor activities both
tyrosine kinases and protein kinase C and that protein kinase C activation
is important for the stimulation of gene transcription. Finally, we show
that GM-CSF binding stimulates c-jun protooncogene transcription and
activates other genes which contain the AP-1 enhancer sequence. In this proposal, we will (1) examine the role of the secreted receptor in
the biologic activity of this hormone (2) study how tyrosine kinases and
protein kinase C interact to mediate the effects of GM-CSF on transcription
(3) determine whether protein phosphorylation mediated by GM-CSF activates
binding of Fos/Jun proteins to the AP-1 enhancer sequences. In addition we
will map the c-jun enhancer to determine which sequences are necessary for
the transcriptional activation of this gene by GM-CSF. The results of
these studies will illucidate how the binding of GM-CSF to its receptor
functions to mediate gene transcription. By understanding the early events
stimulated by GM-CSF, we would hope to better understand how this agent
stimulates growth and differentiation of hematopoietic cells. This
knowledge will enable us to use this agent more effectively in the
treatment of disease and to block its activity when it functions to promote
the growth of neoplastic cells.
StatusFinished
Effective start/end date3/1/9211/30/01

Funding

  • National Institutes of Health: $235,703.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Granulocyte-Macrophage Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Protein Kinases
Cell Line
Growth
Cell Differentiation
Genes
Signal Transduction
Interleukin-3
Transcription Factor AP-1
Phosphorylation
Phosphotransferases
Proteins
Juvenile Myelomonocytic Leukemia
Amino Acids

ASJC

  • Medicine(all)