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Falkor, a novel cell growth regulator isolated by a functional genetic screen
Neta Erez1, Michael Milyavsky, Naomi Goldfinger
1Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel 76100.
Abstract:
A novel cell growth regulator, named Falkor, was identified using a functional approach to mammalian gene cloning, the Genetic Supressor Elements (GSE) method. In this screen, expression of the C-terminal domain of Falkor conferred cells with resistance to cisplatin-induced growth arrest. Expression of the C-terminus of Falkor, but not of the full-length protein, enhanced cell growth both following genotoxic stress and under normal conditions suggesting a general role for this protein in cell growth control. This effect of the C-terminus fragment was abrogated by over-expression of the full-length Falkor, suggesting that the fragment counteracts the function of the full-length protein. Falkor is encoded by a 2-kb mRNA which is present at different levels in various tissues, and is localized in the nucleus of cells. The C-terminal domain of Falkor, isolated from the GSE library, has significant homology to a known human and rat cell growth regulator, SM-20, and to the C. elegans protein EGL-9, recently shown to modify the Hypoxia Inducible Factor-1alpha. The homology suggests that these proteins share a functional domain that is conserved among a family of growth regulation proteins.
Insights
A novel cell growth regulator, Falkor, was discovered. Its C-terminal domain promotes cell growth, counteracting the full-length protein and suggesting a conserved family of growth regulators.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cell growth regulation is crucial for development and disease.
- Identifying novel regulators of cell proliferation is a key area of research.
- The Genetic Supressor Elements (GSE) method offers a functional approach to gene discovery.
Purpose of the Study:
- To identify novel mammalian cell growth regulators.
- To characterize the function of a newly identified protein, Falkor.
- To investigate the role of Falkor's domains in cell growth control.
Main Methods:
- Functional screening using the Genetic Supressor Elements (GSE) method for mammalian gene cloning.
- Expression of Falkor domains (full-length and C-terminal) in cells.
- Assessing cell growth under normal and genotoxic stress conditions.
- Comparative sequence analysis to identify homologous proteins.
Main Results:
- A novel cell growth regulator, Falkor, was identified via GSE screening.
- Expression of Falkor's C-terminal domain enhanced cell growth, even under genotoxic stress.
- The C-terminal domain's growth-promoting effect was inhibited by full-length Falkor, indicating functional antagonism.
- Falkor mRNA is expressed in various tissues and the protein localizes to the nucleus.
- The Falkor C-terminus shows homology to known growth regulators SM-20 and EGL-9, suggesting a conserved functional domain.
Conclusions:
- Falkor is a novel cell growth regulator with a functional C-terminal domain.
- The C-terminus of Falkor antagonizes the full-length protein's function, playing a key role in cell growth control.
- Falkor belongs to a conserved family of growth regulation proteins, potentially linked to pathways like Hypoxia Inducible Factor-1alpha.
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