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LUCA15, a putative tumour suppressor gene encoding an RNA-binding nuclear protein, is down-regulated in
1Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Background:
The proliferation of mammalian cells is controlled by various intracellular mitogenic signalling pathways. In the intracellular pathways, Ras is involved in the activation of proto-oncogenes such as an immediate early gene c-fos. The somatic mutations of ras genes that elicit the constitutive activation of Ras have been found in tumours. Although these findings suggest that the constitutive activation of Ras-mediated pathways alters the expression of a set of genes involving tumorigenesis, these genes have not yet fully been studied.
Results:
To study the up- or down-regulated genes in ras-transformed cells, we analysed Rat-1 transfectants expressing Ras(G12V) mutant protein in response to isopropyl-1-beta-thio-D-galactoside using a differential display. We found that the mRNA level of rat homologue of LUCA15, which has been cloned initially as a putative tumour suppressor gene mapped on human chromosome 3, was down-regulated by the expression of Ras(G12V). Epitope-tagged LUCA15 protein was localized in nuclei and had the ability to bind poly(G) RNA homopolymers in vitro. Moreover, ectopic expression of LUCA15 in human fibrosarcoma HT1080 cells suppressed the cell growth.
Conclusion:
These results demonstrate that LUCA15 is one of the down-regulated genes in ras-transformed cells, and suggests that LUCA15 may function as a negative regulator of cell proliferation by the alteration of its mRNA level.
Insights
Ras-mediated pathways can alter gene expression in tumors. This study found that LUCA15, a potential tumor suppressor, is down-regulated in ras-transformed cells, suggesting it may inhibit cell proliferation.
Area of Science:
- Cell biology
- Molecular oncology
- Gene regulation
Background:
- Mammalian cell proliferation is regulated by intracellular mitogenic signaling pathways, including Ras.
- Ras pathway activation, often due to ras gene mutations, is implicated in tumorigenesis.
- The specific genes altered by constitutive Ras activation in cancer remain incompletely understood.
Purpose of the Study:
- To identify genes that are up- or down-regulated in cells with activated Ras.
- To investigate the role of the rat homologue of LUCA15 in ras-transformed cells.
Main Methods:
- Differential display analysis of Rat-1 transfectants expressing Ras(G12V) mutant protein.
- Analysis of LUCA15 protein localization and RNA binding in vitro.
- Assessment of LUCA15's effect on cell growth via ectopic expression in human fibrosarcoma cells.
Main Results:
- The mRNA level of the rat homologue of LUCA15 was significantly down-regulated by Ras(G12V) expression.
- Ectopic expression of LUCA15 suppressed cell growth in human fibrosarcoma HT1080 cells.
- LUCA15 protein localizes to the nucleus and binds poly(G) RNA homopolymers.
Conclusions:
- LUCA15 is identified as a down-regulated gene in ras-transformed cells.
- LUCA15 may function as a negative regulator of cell proliferation.
- Alterations in LUCA15 mRNA levels are linked to ras-mediated cellular changes.