title: The interplay between p16 serine phosphorylation and arginine methylation determines its function in modulating cellular apoptosis and senescence.
abstract: Cyclin-dependent kinase inhibitor p16INK4a(p16) primarily functions as a negative regulator of the retinoblastoma protein (Rb) -E2F pathway, thus plays critical role in cell cycle progression, cellular senescence and apoptosis. In this study, we showed that the methylation of Arg 138 and the phosphorylation of Ser 140 on p16 were critical for the control of cell proliferation and apoptosis. Compared to wild type p16, mutant p16R138K possessed improved function in preventing cell proliferation and inducing apoptosis, while the Ser 140 mutation (p16S140A) exhibited the opposite alteration. We also demonstrated that H2O2was able to induce the phosphorylation of p16, which facilitated the interaction between CDK4 (Cyclin-dependent protein kinase) and p16, in 293T (human emborynic kidney) cells. Furthermore, the elevated arginine methylation in p16S140A mutant and increased serine phosphorylation in p16R138K mutant suggest that a antagonizing mechanism coordinating Arg 138 methylation and Ser 140 phosphorylation to regulates p16 function as well as cellular apoptosis and senescence. These findings will therefore contribute to therapeutic treatment for p16-related gene therapy by providing theoretical and experimental evidence.
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, P. R. China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Ma
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, P. R. China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, P. R. China.|School of Life Sciences, Northeast Normal University, Changchun 130024, P. R. China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001120:Arginine / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008745:Methylation; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050505:Mutant Proteins; D010768:Phosphoserine; D012694:Serine; D001120:Arginine; D006861:Hydrogen Peroxide; D051358:Cyclin-Dependent Kinase 4