MECHANISMS FOR CONTROL OF CELL GROWTH BY GAP JUNCTIONS

  • Nicholson, Bruce J (PI)

Project: Research project

Project Details

Description

The direct metabolic and electrical coupling of cells by means of
gap junctions has far significance for the integration of tissue
function as a whole and specific relevance to the regulation of
cell proliferation. Tumor and transformed cells typically show
reduced coupling and many transforming agents (eg. oncogenes, tumor
promotors) seem to down-regulate junctional expression. The
reverse has also been reported for some anti-neoplastic agents (eg.
retinoic acid). Clones (cDNA) to several of the known gap junction proteins have
now been isolated and clearly show there to be a family of related
proteins showing major differences in their regulatory domains.
As a first step, the gap junctional channel structure and locations
of functional domains on the protein subunits will be studied and
compared between the various subtypes. Initial models will be
tested and modified using results from in vitro manipulations (eg.
phosphorylation), peptide analyses, and site specific antibodies.
Functional effects on the junctions will be monitored
electrophysiologically in isolated preparations employing the "tip-
patch" technique, or in situ in cultured cells. Refinement of
these models will be achieved by expression of the proteins in frog
oocytes, and subsequently testing the effects of oligonucleotide
directed mutations on intercellular channel function. These
studies will serve to better describe channel structure,
selectivity (if found in the various subtypes) and modes of
regulation. Parallel experiments will use conserved and variable region probes
from the junctional cDNA's to determine the approximate size of the
gene family and the patterns of expression of the different
junction subtypes before and after the transformation process,
including their distribution within selected tumors. Finally, the
two lines of investigation will be combined by transforming cells
with expression vectors containing the junctional cDNA's (in both
sense and antisense orientations) and directly testing the
necessity or sufficiency of junctional downregulation in the
process of transformation and metastatic invasion of issue.
StatusFinished
Effective start/end date1/1/896/30/06

Funding

  • National Institutes of Health: $264,909.00
  • National Institutes of Health
  • National Institutes of Health: $177,507.00
  • National Institutes of Health: $144,516.00
  • National Institutes of Health
  • National Institutes of Health: $257,195.00
  • National Institutes of Health
  • National Institutes of Health: $153,120.00
  • National Institutes of Health: $255,420.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $217,983.00
  • National Institutes of Health: $125,453.00

ASJC

  • Medicine(all)

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