title: Ablation of galectin-3 induces p27(KIP1)-dependent premature senescence without oncogenic stress.
abstract: Premature senescence induced by oncogenic stimuli or tumor suppressor activation plays opposing roles in tumorigenesis. Here, we propose that galectin-3, a β-galactoside-binding lectin, regulates premature senescence without oncogenic stress. We detected premature senescence, decreased Skp2, and increased p27(KIP1) expression in galectin-3 knockout MEFs and galectin-3-depleted gastric cancer cells. Interestingly, galectin-3 depletion did not affect other senescence inducers such as p14(ARF), p16(INK4A), and p21(WAF1/CIP1), suggesting that galectin-3-regulated senescence is p27(KIP1) dependent. We demonstrate that galectin-3 depletion decreases retinoblastoma protein (Rb) phosphorylation (Ser780, Ser807/811), cyclin D1 and CDK4 expression, and E2F1 transcriptional activation. Galectin-3 directly interacts with the cyclin D1/CDK4 complex and promotes hyperphosphorylation of Rb. It also blocks the inhibition of E2F1 transcription, thereby increasing the expression of Skp2 and reducing the stability of p27(KIP1) to promote the proliferation of gastric cancer cells. Xenograft mice with galectin-3-depleted gastric cancer cells display tumor growth retardation that is reversed by Skp2 overexpression. Increased expression of galectin-3 is also associated with the advanced TNM (tumor, lymph node, metastasis) system, clinicopathological stage, and lymph node metastases. The probability of survival was significantly decreased in gastric cancer patients with galectin-3(high) p27(KIP1-low)cells. Taken together, our results show that galectin-3 may accelerate gastric tumorigenesis by inhibiting premature senescence.
authors: 1] Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea [2] Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
authors: S-J
authors: SJ
authors: Kim
authors: 1] Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea [2] Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: H-W
authors: HW
authors: Lee
authors: 1] Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea [2] Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
authors: H
authors: H
authors: Gu Kang
authors: 1] Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea [2] Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: S-H
authors: SH
authors: La
authors: Center for Gastric Cancer, National Cancer Center Research Institute, Goyang, Republic of Korea.
authors: Il Ju
authors: IJ
authors: Choi
authors: The Methodist Hospital, Department of Pathology and Genomic Medicine, Weill Medical College of Cornell University, Houston, TX, USA.
authors: J Y
authors: JY
authors: Ro
authors: Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors: R S
authors: RS
authors: Bresalier
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: J
authors: J
authors: Song
authors: 1] Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea [2] Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
authors: K-H
authors: KH
authors: Chun
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009857:Oncogenes; D016160:Retinoblastoma Protein / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D037502:Galectin 3; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases