Coordination of Proliferation and Apoptosis

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):

In 1987, we published the first large scale screen of gene expression in
normal and neoplastic colonic tissue, encompassing quantitative analysis of
each of 4,000 cloned sequences. This led to the discovery that a coordinated
decrease of the expression of the mitochondrial genome characterized the
colonic mucosa at risk as well as colon tumors, with a return to normal levels
of expression upon induction of cell maturation with a physiological regulator
of cell maturation in the colon, the short-chain fatty acid butyrate (NaB).
Subsequent papers dissected the role of mitochondrial function in colonic cell
maturation, including apoptosis, and in 1998 we suggested that "the
mitochondria may be the final integration site of multiple signals, which
ultimately coordinate proliferation and apoptosis pathways".

This application is to determine if TR3 (Nurr77), an orphan steroid receptor,
plays a central role in this coordination achieved by the short-chain fatty
acid butyrate. It has recently been demonstrated that TR3 resides in the
nucleus and functions as a transcription factor during cell growth, but that
apoptotic stimuli cause its translocation to the mitochondrial membrane, where
it mediates release of cytochrome c and hence initiation of an apoptotic
cascade. We will determine: 1) the effects of butyrate on expression and
sub-cellular localization of TR3 in colonic cell lines that differ in their
p53 and c-myc status; 2) how modulation of mitochondrial function and/or
collapse of the membrane potential affects nuclear - mitochondrial
translocation; 3) utilizing isogenic cell lines, how the presence of an
activated k-ras allele, which is necessary for the butyrate stimulation of
apoptosis, is linked to the expression and translocation of TR3; 4) how
genetic manipulation in vivo alters expression and sub-cellular distribution
of TR3 in relation to cell position along the crypt-lumen axis. These last
experiments will make use of banked tissue from mouse experiments which have
already reported the effect of targeted inactivation of Apc and p21 WAFl/cipl
and a homozygous deletion for scad (short-chain acyl dehydrogenase), on
mucosal apoptosis and proliferation in the duodenum, proximal and distal
colon. Understanding the mechanism by which mitochondrial function coordinates
cell maturation pathways in the intestinal mucosa has profound implications
for understanding tumorigenesis and for effecting chemoprevention.
StatusFinished
Effective start/end date7/1/016/30/02

Funding

  • National Cancer Institute: $63,243.00

ASJC

  • Biochemistry
  • Cancer Research
  • Cell Biology
  • Histology
  • Developmental Biology

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.