title: Tumor suppressor p16(INK4a) inhibits cancer cell growth by downregulating eEF1A2 through a direct interaction.
abstract: The tumor suppressor protein p16(INK4a) is a member of the INK4 family of cyclin-dependent kinase (Cdk) inhibitors, which are involved in the regulation of the eukaryotic cell cycle. However, the mechanisms underlying the anti-proliferative effects of p16(INK4a) have not been fully elucidated. Using yeast two-hybrid screening, we identified the eukaryotic elongation factor (eEF)1A2 as a novel interacting partner of p16(INK4a). eEF1A2 is thought to function as an oncogene in cancers. The p16(INK4a) protein interacted with all but the D2 (250-327 aa) domain of eEF1A2. Ectopic expression of p16(INK4a) decreased the expression of eEF1A2 and inhibited cancer cell growth. Furthermore, suppression of protein synthesis by expression of p16(INK4a) ex vivo was verified by luciferase reporter activity. Microinjection of p16(INK4a) mRNA into the cytoplasm of Xenopus embryos suppressed the luciferase mRNA translation, whereas the combination of p16(INK4a) and morpholino-eEF1A2 resulted in a further reduction in translational activity. We conclude that the interaction of p16(INK4a) with eEF1A2, and subsequent downregulation of the expression and function of eEF1A2 is a novel mechanism explaining the anti-proliferative effects of p16(INK4a).
authors: The Hormel Institute, University of Minnesota, MN 55912, USA.
authors: Mee-Hyun
authors: MH
authors: Lee
authors: Bu Young
authors: BY
authors: Choi
authors: Yong-Yeon
authors: YY
authors: Cho
authors: Sung-Young
authors: SY
authors: Lee
authors: Zunnan
authors: Z
authors: Huang
authors: Joydeb Kumar
authors: JK
authors: Kundu
authors: Myoung Ok
authors: MO
authors: Kim
authors: Dong Joon
authors: DJ
authors: Kim
authors: Ann M
authors: AM
authors: Bode
authors: Young-Joon
authors: YJ
authors: Surh
authors: Zigang
authors: Z
authors: Dong
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D020648:Peptide Elongation Factor 1 / Q000378:metabolism*; D011485:Protein Binding; D020798:Two-Hybrid System Techniques; D014982:Xenopus laevis
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C503234:EEF1A2 protein, human; D020648:Peptide Elongation Factor 1
keywords: Anti-proliferative effects; Ovarian cancer; Translational activity; eEF1A2; p16INK4a