title: Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage.
abstract: Synthesis of the p53 tumor suppressor and its subsequent activation following DNA damage are critical for its protection against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) at the 5' untranslated region of the p53 mRNA. However, the connection between IRES-mediated p53 translation and p53's tumor suppressive function is unknown. In this study, we identified two p53 IRES trans-acting factors, translational control protein 80 (TCP80), and RNA helicase A (RHA), which positively regulate p53 IRES activity. Overexpression of TCP80 and RHA also leads to increased expression and synthesis of p53. Furthermore, we discovered two breast cancer cell lines that retain wild-type p53 but exhibit defective p53 induction and synthesis following DNA damage. The levels of TCP80 and RHA are extremely low in both cell lines, and expression of both proteins is required to significantly increase the p53 IRES activity in these cells. Moreover, we found cancer cells transfected with a shRNA against TCP80 not only exhibit decreased expression of TCP80 and RHA but also display defective p53 induction and diminished ability to induce senescence following DNA damage. Therefore, our findings reveal a novel mechanism of p53 inactivation that links deregulation of IRES-mediated p53 translation with tumorigenesis.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Marie-Jo
authors.initials: MJ
authors.lastname: Halaby
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: Benjamin R E
authors.initials: BR
authors.lastname: Harris
authors.affiliation: Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, South Dakota, USA.
authors.forename: W Keith
authors.initials: WK
authors.lastname: Miskimins
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Margot P
authors.initials: MP
authors.lastname: Cleary
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota, USA The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA dyang@hi.umn.edu.
authors.forename: Da-Qing
authors.initials: DQ
authors.lastname: Yang
mesh_terms: D020121:5' Untranslated Regions; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D050779:Nuclear Factor 90 Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D059748:Proteolysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C429643:ILF3 protein, human; D000067556:Internal Ribosome Entry Sites; D009363:Neoplasm Proteins; D050779:Nuclear Factor 90 Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C098487:DHX9 protein, human; D053487:DEAD-box RNA Helicases