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Loss of Cyclin G1 Expression in Human Uterine Leiomyoma Cells Induces Apoptosis

Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, chcho{at}kmu.ac.kr

Joon-Cheol Park, MD

Department of Obstetrics and Gynecology, School of Medicine, Keimyung University

Sabarish Ramachandran, MS

Department of Obstetrics and Gynecology, School of Medicine, Keimyung University

Soon-Do Cha, MD

Department of Obstetrics and Gynecology, School of Medicine, Keimyung University

Kun-Young Kwon, MD

Department of Pathology School of Medicine, Keimyung University, Daegu, Korea

Jong-Ku Park, PhD

Chronic Disease Research Center and Institute for Medical Science, Keimyung University, Daegu, Korea

Jong-Wook Park, MD

Chronic Disease Research Center and Institute for Medical Science, Keimyung University, Daegu, Korea

Insoo Bae, PhD

Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC

Chi-Heum Cho, MD

Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, Chronic Disease Research Center and Institute for Medical Science, Keimyung University, Daegu, Korea

Observations from the authors' laboratory suggest a physiological role for increased cyclin G1 protein levels in human uterine leiomyoma. The hypothesis of the present study is that the strategic modulation of cyclin G1 by antisense technology will inhibit the survival of in vitro—grown uterine leiomyoma cells. Cultured uterine leiomyoma cells were transfected with cyclin G1 ribbon-type antisense oligonucleotide (cyclin G1 RiAS) to effectively reduce cyclin G1 expression. Cell viability, in situ terminal deoxyuridine nick end-labeling (TUNEL) assay, flow cytometry, DNA fragmentation, and expression of cell cycle regulatory—related proteins were evaluated by Western blot. Antisense oligonucleotides compromised uterine leiomyoma cell viability and inducted apoptosis in a caspase-independent mechanism. In situ TUNEL and DNA fragmentation revealed apoptosis induction, and fluorescent-activated cell sorting analysis showed increased sub-G1-phase cells. Furthermore, abrogation of cyclin G1 enhanced p53 accumulation, phosphorylation of p53 at Ser-15 residue, and increased expression of cyclin-dependent kinase inhibitors p21 and p27. These data imply that cyclin G1 expression is associated with growth promotion and the potential utility and novelty of using ribbon-type antisense oligonucleotides as a gene therapy strategy to treat human uterine leiomyoma.

Key Words: Uterine leiomyoma • cyclin G1 • cyclin G1 ribbon—type antisense oligonucleotides • p53 • apoptosis.

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