title: Endogenous LKB1 knockdown accelerates G(1)/S transition through p53 and p16 pathways.
abstract: The tumor suppressor LKB1 is inactivated in 90% of Peutz-Jeghers cancer syndrome, 30-40% of non-small cell lung carcinoma, and a variety of other cancers, indicating the loss of LKB1 activity is a critical step in oncogenesis. However, current understanding of LKB1 function is largely limited to the results from cancer cells, and how LKB1 inactivation initiates malignant transformation in normal cells remains unclear. Here we ablated endogenous expression of LKB1 in two normal cell lines: human embryonic kidney 293T cells (HEK-293T cells) and human umbilical vein endothelial cells (HUVECs) by LKB1-specific short hairpin RNAs. Downregulation of endogenous LKB1 lead to a facilitated G(1)/S transition, accompanied by a concomitant increase in Rb phosphorylation (Ser(807/811)). Furthermore, reduced expression of p53 and p16 was observed in LKB1 ablated cells, while no differences were detected for cyclin D1 and cyclin E. These results jointly suggest that endogenous LKB1 knockdown accelerates cell cycle progression through G(1)/S checkpoint in HEK-293T cells and HUVECs, which is at least in part, mediated by decline of p53 and p16 pathways. Our findings provided a plausible mechanism by which loss of LKB1 expression in normal cells contributes to the formation of malignancies.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liang
authors.forename: Pilong
authors.initials: P
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Tao
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000502:physiology*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D055785:Gene Knockdown Techniques; D019942:Genes, p16; D016158:Genes, p53; D007668:Kidney; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014471:Umbilical Veins
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases