Translational Control Protein 80 Stimulates IRES-Mediated Translation of p53 mRNA in Response to DNA Damage.
Synthesis of the p53 tumor suppressor increases following DNA damage. This increase and subsequent activation of p53 are essential for the protection of normal cells against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) that is located at the 5'-untranslated region (UTR) of p53 mRNA and found that the IRES activity increases following DNA damage. However, the mechanism underlying IRES-mediated p53 translation in response to DNA damage is still poorly understood. In this study, we discovered that translational control protein 80 (TCP80) has increased binding to the p53 mRNA in vivo following DNA damage. Overexpression of TCP80 also leads to increased p53 IRES activity in response to DNA damage. TCP80 has increased association with RNA helicase A (RHA) following DNA damage and overexpression of TCP80, along with RHA, leads to enhanced expression of p53. Moreover, we found that MCF-7 breast cancer cells with decreased expression of TCP80 and RHA exhibit defective p53 induction following DNA damage and diminished expression of its downstream target PUMA, a proapoptotic protein. Taken together, our discovery of the function of TCP80 and RHA in regulating p53 IRES and p53 induction following DNA damage provides a better understanding of the mechanisms that regulate IRES-mediated p53 translation in response to genotoxic stress.
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Marie-Jo
MJ
Halaby
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Yan
Y
Li
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Benjamin R
BR
Harris
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Shuxia
S
Jiang
Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57104, USA.
W Keith
WK
Miskimins
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA ; The Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Margot P
MP
Cleary
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA ; The Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Da-Qing
DQ
Yang
D004249:DNA Damage / Q000502:physiology*; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000502:physiology*; D061986:MCF-7 Cells; D050779:Nuclear Factor 90 Proteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C429643:ILF3 protein, human; D000067556:Internal Ribosome Entry Sites; D050779:Nuclear Factor 90 Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53