title: BMI-1 interacts with sMEK1 and inactivates sMEK1-induced apoptotic cell death.
abstract: The B lymphoma Mo-MLV insertion region 1 homolog (BMI-1) protein is activated in various types of tumors and associated with cancer development and tumor progression. However, the working role of BMI-1 in cellular signaling is not understood completely. In this study, we revealed one possible biologic mechanism of BMI-1 in cancer progression in vitro using a human ovarian tumor cell system. Suppressor of MEK1 (sMEK1), a pivotal regulator involved in the cellular biological response mechanism, was identified as a BMI-1-binding protein. Ectopic expression of BMI-1 activated cell growth by reducing sMEK1-stimulated apoptotic cell death and suppressing p21, p27 and p53 expression, while enhancing cyclin D1, CDK4 and Bcl-2 expression. The effect of BMI-1 on cell cycle and apoptotic regulatory proteins was also confirmed via silencing of BMI-1 expression. Subsequently, the promoter activities of p21 and p53 were inactivated significantly. However, BMI-1 overexpression noticeably increased Bcl-2 and NF-κB activities. In addition, BMI-1 activated the PI3K/mTOR/4E-BP1 signaling pathways, and sMEK1 significantly inhibited BMI-1-stimulated oncogenesis. These insights provide evidence that BMI-1 activates cell growth and suppresses apoptosis. Collectively, our data indicate that BMI-1 plays a pivotal role in the progression of ovarian cancer, thus representing a novel target for antitumor therapy of ovarian cancer.
authors.affiliation: Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014162:Transfection
chemical_list: C069077:BMI1 protein, human; D063150:Polycomb Repressive Complex 1; C573787:PPP4R3A protein, human; D010749:Phosphoprotein Phosphatases