RAF KINASE AND CELL PROLIFERATION

  • Farnham, Peggy, (PI)

Project: Research project

Description

Progression of cells through the cell division cycle is controlled by
interconnecting signal transduction pathways that result in transient
activation and repression of growth-responsive any step in the pathway
depends on the completion of a prior step, thus providing multiple points
where the cascade can be blocked. A detailed understanding of the
regulatory pathways of neoplastic cells. The first step towards
controlling cell growth is to identify pathways, which when deregulated,
lead to neoplasia. One such pathway contains the c-raf gene. c-RAF is
a serine/threonine kinase that can be activated by over a dozen different
mitogens, suggesting that c-RAF is of central importance in cell growth.
In fact, studies of c-RAF function have shown a correlation between c-RAF
activation and transformation and between c-RAF inhibition and
constraints on cell growth. Because c-RAF function will have pleiotropic
effects on cell growth and is unlikely to lead to useful therapeutic
intervention. What is required is to understand the individual pathways
leading from c-RAF so that specific neoplastic properties of transformed
cells can reverted. Therefore, a logical second step is to identify cell
cycle-regulated genes that are indirectly controlled by c-RAF activation.
We have shown that constitutive expression of an activated v-RAF in
quiescent cells is sufficient to elicit an increase in transcription from
both early (egr2) and late (cad ad rep-3b) serum-response genes.
However, several important questions are left unresolved by these
experiments. First, it is not known if c-RAF is involved in the normal
activation of theses promoters after growth stimulation. Second, a
complete c-RAF-activated pathway from early to late response promoters
has not yet been traced. To answer these questions, we propose to
determine if c-RAF is critical for the cell cycle-regulated
transcriptional activation of v-RAF responsive promoters (Specific Aim
1), to determine the role of the early response EGR2 transcription factor
in cell proliferation and in the activation of the late response cad or
rep-3b (Specific Aim 2), and to characterize the activation of the late
response cad or rep-3b promoters (Specific Aim 3). Our preliminary
experiments have identified several new components (EGR2,REP-3b, and CAD)
of an important signal transduction pathway. Our proposed experiments
will attempt to connect the individual members to other components of the
c-RAF pathways. Using the knowledge gained in these experiments, we can
direct our future experiments toward specific inactivation of different
components of the pathway. These future studies should provide insight
about novel ways to revert specific neoplastic properties of transformed
cells.
StatusFinished
Effective start/end date3/15/941/31/97

Funding

  • National Institutes of Health
  • National Institutes of Health: $141,862.00
  • National Institutes of Health: $149,854.00

Fingerprint

raf Kinases
Cell Proliferation
Growth
Phosphotransferases
Signal Transduction
Cell Cycle
Early Growth Response Protein 2
Protein-Serine-Threonine Kinases
Genes
cdc Genes
Mitogens
Transcriptional Activation
Serum
Neoplasms

ASJC

  • Medicine(all)