INTRACELLULAR MEDIATORS OF TGF EFFECTS

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the applicant's abstract): TGFbeta-based
therapeutics may potentially be successful against epithelial cancers,
since this autocrine polypeptide regulator inhibits the proliferation of
responsive carcinoma cells and elicits differentiation-like effects.
However, the signaling pathway(s) leading to the growth inhibitory
effect of TGFbeta have not been elucidated. The principal
investigator's previous data provided the first direct evidence for
rapid activation of cytoplasmic signaling components (Ras and the
mitogen-activated protein kinse ERK1) by TGFbeta in association with
growth inhibition. Additional data suggests that the effects of TGFbeta
on cell cycle components may also play a role in the growth inhibitory
response to TGFbeta. The principal investigator hypothesizes that
TGFbeta activation of ERK1 is upstream from the effects of TGFbeta on
nuclear cell cycle components in the TGFbeta signaling pathway.
Accordingly, the principal investigator will examine whether the
activation of ERK1 by TGFbeta kinetically precedes the effects of TGFbeta
on complexes between cyclins and cyclin-dependent kinases (Cdk's) in the
nucleus. It is further hypothesized that the cytoplasmic and nuclear
components modulated by TGFbeta may be linked in a manner analogous to
that demonstrated in yeast with regard to the growth inhibitory effects
of mating pheromones. That is, the MapK cascade in yeast directly leads
to phosphorylation and transcriptional activation of a Cdk inhibitor
(FAR1). Thus the principal investigator plans to investigate whether
TGFbeta regulation of mammalian Cdk inhibitor p27Kip1 kinetically
follows TGFbeta activation of ERK1 in asynchronous cultures of epithelial
cells.
StatusFinished
Effective start/end date5/1/962/28/01

Funding

  • National Cancer Institute

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