Inhibitory action of polyunsaturated fatty acids on Cdt1-geminin interaction. 2008

Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp

A human replication initiation protein, Cdt1, is a central player in the cell cycle regulation of DNA replication, and geminin down-regulates Cdt1 function by direct binding. It has been demonstrated that Cdt1 hyperfunction resulting from Cdt1-geminin imbalance, for example, by geminin silencing with small interfering RNA, induces DNA re-replication and eventual cell death in some cancer-derived cell lines. We established a high throughput screening system based on a modified enzyme-linked immunosorbent assay to identify compounds that interfere with human Cdt1-geminin binding. Using this system, we screened inhibitors from natural compounds, and found that a fatty acid, linoleic acid (C18:2), from a basidiomycete, inhibited Cdt1-geminin interaction in vitro. Of the commercially purchased linear-chain fatty acids tested, the inhibitory effect of oleic acid (C18:1) was the strongest, with 50% inhibition observed at concentrations of 9.6 microM. Since trans-configuration, the ester form, and the addition of the hydroxyl group of oleic acid had no influence on C18:1 fatty acid derivatives, both parts of a carboxylic acid and an alkyl chain containing cis-type double bonds of fatty acid might be essential for inhibition. Surface plasmon resonance analysis demonstrated that oleic acid was able to bind selectively to Cdt1, but did not interact with geminin. Using a three-dimensional computer modeling analysis, oleic acid was conjectured to interact with the geminin interaction interface on Cdt1, and the carboxyl group of oleic acid was assumed to form hydrogen bonds with the residue of Arg342 of Cdt1. These results suggested that, at least in vitro, oleic acid-containing cell membranes of the lipid bilayer inhibit Cdt1-geminin complex formation by binding to Cdt1 and thereby liberating Cdt1 from inhibition by geminin.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D009687 Nuclear Proteins Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. Nucleolar Protein,Nucleolar Proteins,Nuclear Protein,Protein, Nuclear,Protein, Nucleolar,Proteins, Nuclear,Proteins, Nucleolar
D011092 Polyethylene Glycols Polymers of ETHYLENE OXIDE and water, and their ethers. They vary in consistency from liquid to solid depending on the molecular weight indicated by a number following the name. They are used as SURFACTANTS, dispersing agents, solvents, ointment and suppository bases, vehicles, and tablet excipients. Some specific groups are NONOXYNOLS, OCTOXYNOLS, and POLOXAMERS. Macrogols,Polyoxyethylenes,Carbowax,Macrogol,Polyethylene Glycol,Polyethylene Oxide,Polyethyleneoxide,Polyglycol,Glycol, Polyethylene,Glycols, Polyethylene,Oxide, Polyethylene,Oxides, Polyethylene,Polyethylene Oxides,Polyethyleneoxides,Polyglycols,Polyoxyethylene
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D003198 Computer Simulation Computer-based representation of physical systems and phenomena such as chemical processes. Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins
D005231 Fatty Acids, Unsaturated FATTY ACIDS in which the carbon chain contains one or more double or triple carbon-carbon bonds. Fatty Acids, Polyunsaturated,Polyunsaturated Fatty Acid,Unsaturated Fatty Acid,Polyunsaturated Fatty Acids,Acid, Polyunsaturated Fatty,Acid, Unsaturated Fatty,Acids, Polyunsaturated Fatty,Acids, Unsaturated Fatty,Fatty Acid, Polyunsaturated,Fatty Acid, Unsaturated,Unsaturated Fatty Acids
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012710 Serum Albumin, Bovine Serum albumin from cows, commonly used in in vitro biological studies. (From Stedman, 25th ed) Fetal Bovine Serum,Fetal Calf Serum,Albumin Bovine,Bovine Albumin,Bovine Serum Albumin,Albumin, Bovine,Albumin, Bovine Serum,Bovine Serum, Fetal,Bovine, Albumin,Calf Serum, Fetal,Serum, Fetal Bovine,Serum, Fetal Calf
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

Related Publications

Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
January 1971, Acta vitaminologica et enzymologica,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
January 1975, International archives of allergy and applied immunology,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
September 2003, Nihon rinsho. Japanese journal of clinical medicine,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
November 2006, Life sciences,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
May 2009, American journal of physiology. Cell physiology,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
August 1993, Nihon rinsho. Japanese journal of clinical medicine,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
May 2015, Genes,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
January 2012, Sub-cellular biochemistry,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
May 1960, La Clinica terapeutica,
Yoshiyuki Mizushina, and Toshifumi Takeuchi, and Yoichi Takakusagi, and Fumio Sugawara, and Kengo Sakaguchi, and Hiromi Yoshida, and Masatoshi Fujita
October 2010, Progress in lipid research,
Copied contents to your clipboard!