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Cell Death, Cell Cycle and Senescence

Ectopic Expression of 10-Formyltetrahydrofolate Dehydrogenase in A549 Cells Induces G₁ Cell Cycle Arrest and Apoptosis¹

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC

Requests for reprints: Sergey A. Krupenko, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Room 512-B BSB, Charleston, SC 29425. Phone: (843) 792-0845; Fax: (843) 792-8565. E-mail: krupenko{at}musc.edu

We have recently shown that transient expression of 10-formyltetrahydrofolate dehydrogenase (FDH) strongly inhibits proliferation of several cancer cell lines and ultimately results in cell death. In the present studies using Tet-On system, we have generated a stable A549 lung carcinoma cell line capable of inducible FDH expression. Using this system, we were able to express FDH at different levels depending on concentration of the inducer, doxycycline, and we have observed that inhibition of proliferation depends on FDH intracellular levels. We have further shown that induction of FDH expression results in initiation of apoptosis beginning 24 h post-induction. Apoptotic cells revealed cleavage of poly-(ADP-ribose) polymerase and general caspase inhibitor zVAD-fmk protected cells against FDH-induced apoptosis. FDH-expressing cells showed accumulation of cells in G₀-G₁ phase and a sharp decrease of cells in S phase. Accumulation of intracellular FDH was followed by accumulation of the tumor suppressor protein p53 and its downstream target p21. These results indicate that FDH antiproliferative effects on A549 cells include both G₁ cell cycle arrest and caspase-dependent apoptosis.

This article has been cited by other articles:

				S. N. Reuland, A. P. Vlasov, and S. A. Krupenko Modular organization of FDH: Exploring the basis of hydrolase catalysis Protein Sci., May 1, 2006; 15(5): 1076 - 1084. [Abstract] [Full Text] [PDF]