Polypyrimidine tract binding protein regulates IRES-mediated translation of p53 isoforms.
The p53 tumor suppressor protein plays a key role in maintaining genomic integrity. Enhanced expression of p53 during genotoxic stress is due to both increased protein stability and translational upregulation. Previous reports have shown that p53 mRNA is translated from an alternative initiation codon to produce N-terminal truncated isoform (DeltaN-p53) besides full-length p53. We have demonstrated that two internal ribosome entry sites (IRESs) regulate the translation of p53 and DeltaN-p53 in a distinct cell cycle phase-dependent manner. Here, we report that polypyrimidine tract-binding protein (PTB) is a p53 IRES interacting trans-acting factor. PTB protein binds specifically to both the p53 IRESs but with differential affinity. siRNA-mediated knockdown of PTB protein results in reduction of activity of both IRESs and also the levels of both the isoforms. It is well known that DNA-damaging agents such as doxorubicin enhance the expression of p53. Our results indicate that during doxorubicin treatment, PTB protein translocates from nucleus to the cytoplasm, probably to facilitate IRES mediated p53 translation. These observations suggest that the relative cytoplasmic abundance of PTB protein, under DNA-damaging conditions, might contribute to regulating the coordinated expression of the p53 isoforms, owing to the differential affinity of PTB binding to the two p53 IRESs.
Grover
Richa
R
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
Ray
Partho Sarothi
PS
Das
Saumitra
S
D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D020033:Protein Isoforms / Q000096:biosynthesis; D021381:Protein Transport / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D038941:Polypyrimidine Tract-Binding Protein; D004317:Doxorubicin