title: La(3+)-induced extracellular signal-regulated kinase (ERK) signaling via a metal-sensing mechanism linking proliferation and apoptosis in NIH 3T3 cells.
abstract: The effects of La(3+) on the extracellular signal-regulated kinase (ERK) signaling were investigated to explore the mechanism by which La(3+) results in cell proliferation associated with apoptosis in mouse embryo fibroblast NIH 3T3 cells. Our data showed that La(3+) ions could induce a pulse of phosphorylation of ERK mainly through an unknown metal-sensing mechanism, which is different from the Ca(2+)-sensing receptor . The putative sensor protein showed one binding site for La(3+) with a dissociation constant of approximately 8 nM. Inductions of c-fos, c-myc, and cyclin D1 and phosphorylation of retinoblastoma protein (pRb) were observed after activation of ERK. These results are consistent with our previous observation that La(3+) promotes proliferation by helping the cells pass through the G1/S restriction point and enter S phase. This La(3+)-induced signaling cascade exhibited abnormally sustained c-myc induction and pRb phosphorylation. Furthermore, a continual increase of the p53 level was observed along with the signal transduction, and a significant decrease of B-cell lymphoma/leukemia-2 gene was observed after approximately 18 h of incubation. All of the results were highly correlated with the increase of S-phase population and apoptotic cells. Therefore, the experimental results suggested that La(3+) induced cell proliferation and apoptosis compatible to a p53-related mechanism in NIH 3T3 cells via an ERK-signaling cascade induced by a metal-sensing mechanism.
authors.affiliation: Department of Chemical Biology and Joint Laboratory of Peking University and The Hong Kong Polytechnic University, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100083, People's Republic of China.
authors.forename: Siwang
authors.initials: S
authors.lastname: Yu
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Yang
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.forename: Zhong Ming
authors.initials: ZM
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D016762:Genes, fos / Q000235:genetics / Q000502:physiology; D016259:Genes, myc / Q000235:genetics / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology; D007811:Lanthanum / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008670:Metals / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D008670:Metals; D019253:Proto-Oncogene Proteins c-bcl-2; D019938:Cyclin D1; D007811:Lanthanum; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium