(1) Analyses of the CapG tumor suppressor gene
We isolated a series of cell lines from a human diploid fibroblast that had been transformed in various ways; these lines included immortalized, anchorage-independent, and tumorigenic cell lines (Figure). Analysis of their gene expression profiles revealed that the tumorigenic cell line had lost CapG protein expression. Analysis of a variety of cancer cell lines revealed that several had also lost CapG expression. When these tumorigenic human cancer cell lines were transfected with CapG cDNA, they all became non-tumorigenic. We also identified a protein that interacts with CapG: this protein is an oncogene product that forms a complex with another tumor suppressor protein. Thus, CapG may suppress tumorigenicity by modulating the activity of a particular oncoprotein/tumor suppressor protein complex.
(2) Cellular dedifferentiation involved in tumorigenesis
It is well known that cancer cells often express genes that are usually only expressed by less differentiated cells. We found that during the malignant progression of our model cell lines, fibroblast-specific gene expression was shut off and the expression of several new genes was switched on. We are currently studying how the alteration of differentiation status relates to tumorigenesis.
(3) Post-translational regulation of tumor suppressor protein p14ARF by PANO
We isolated a novel apoptosis-inducing gene called PANO, which encodes a nucleolar protein. Our studies then revealed that PANO up-regulates the expression of tumor suppressor protein p14ARF by inhibiting its degradation, and that this may induce apoptosis. We are currently investigating whether this gene participates in human tumorigenesis.