Identification of Junctionally-Transmitted Growth Inhibitors
Abstract
We propose to chemically identify the junctionally transmitted signals which we hypothesize to be responsible for the observed growth inhibition of?east tumor cells when in junctional communication with growth inhibited normal cells. Our previous studies with murine cells have shown that when recently derived, neoplastically transformed fibroblasts were placed in junctional communication with growth inhibited fibroblasts, the transformed fibroblasts were arrested in Gi of the cell cycle. This cell cycle arrest strongly correlated with the degree of junctional communication (1). We lately extended these studies to human epithelial tumor cells in culture and demonstrated that the inducible expression of connexin 43, a gap junction family member expressed in normal epithelial cells but lacking in the carcinoma cells connexin expression resulted in strong attenuation of the neoplastic phenotype. This was detected as a reduction in anchorage independent growth and a reduction in the ability to grow as xenografts in the nude mouse (2). Other investigators have also demonstrated reductions in connexin assembly or expression in neoplastic cells (reviewed in (3)). In several cases, this reduction in expression has been associated with an increase in DNA methylation, a method of gene silencing commonly employed by tumor cells to silence tumor suppressor genes (4). We have hypothesized that growth inhibitory signals can be transferred through gap junctions (5). Because of the physical constraints of the channel formed by a gap junction, these inhibitory signals must be mediated by molecules or ions which are water-soluble and of a size below approximately 1000 daltons (6). Restoration of gap junction function could thus lead to the decreased proliferation of carcinogen-initiated cells thereby reducing their progression to fully transformed cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2002
- Accession Number
- ADB284934
Entities
People
- John S. Hertram
Organizations
- University of Hawaiʻi System