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LOT1 is a growth suppressor gene down-regulated by the epidermal growth factor receptor ligands and encodes a nuclear

A Abdollahi1, R Bao, T C Hamilton

  • 1Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvannia, PA 19111, USA.

Oncogene
|December 22, 1999
PubMed

Insights

The LOT1 gene, often lost in ovarian cancer, acts as a nuclear transcription factor. Its expression inhibits cell proliferation and is regulated by growth factor signaling pathways, suggesting a role in preventing malignant transformation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • The LOT1 gene and its human homolog (hLOT1) were previously identified through differential gene expression analysis.
  • Both human and rat ovarian carcinoma cell lines show reduced or lost LOT1 expression.
  • LOT1 is located on human chromosome 6q25, a region frequently affected by loss of heterozygosity (LOH) in solid tumors, including ovarian cancer.

Purpose of the Study:

  • To further characterize the role of LOT1 in malignant transformation.
  • To investigate LOT1 as a potential target of growth factor signaling pathways.
  • To elucidate the mechanism of LOT1 regulation in ovarian epithelial cells.

Main Methods:

  • Transient transfections to determine LOT1 localization and function.
  • In vitro and in vivo studies using ovarian cancer cell lines.
  • Analysis of Lot1 gene expression in response to growth factors and signaling pathway inhibitors (tyrphostin AG1478, PD098059).

Main Results:

  • LOT1 functions as a nuclear protein, potentially acting as a transcription factor.
  • LOT1 expression is inversely correlated with cellular proliferation and induces morphological transformations in ovarian cancer cells.
  • Lot1 gene expression in normal rat ovarian surface epithelial cells is downregulated by epidermal growth factor receptor (EGFR) ligands (EGF, TGF-alpha) and TPA.
  • Inhibition of EGFR or MEK signaling pathways restores Lot1 expression levels.
  • LOT1 regulation appears specific to EGFR ligands and TPA, with other factors having minimal or transient effects.

Conclusions:

  • LOT1 plays a significant role in inhibiting cellular proliferation and promoting differentiation, acting as a tumor suppressor.
  • LOT1 expression is primarily mediated through the EGFR signaling pathway.
  • LOT1, a zinc-finger motif-containing nuclear transcription factor, may regulate growth-promoting signals and serve as a novel therapeutic target in ovarian cancer.

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