Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate.
Induction of p21 in senescent human fibroblasts plays a key role in the inactivation of cyclin-dependent kinases and the resulting irreversible growth arrest in the early stages of cell senescence. We found that RNA-binding proteins are critical regulators of p21 during senescence. Two RNA-binding proteins, CUGBP1 and calreticulin (CRT), interact with the same nucleotide sequences within the 5' region of p21 mRNA, but have opposite effects on the translation of p21 mRNA. CUGBP1 increases translation of p21 mRNA, whereas CRT blocks translation of p21 via stabilization of a stem-loop structure within the 5' region of the p21 mRNA. CUGBP1 and CRT compete for binding to p21 mRNA and thereby the regulation of p21 translation. In senescent fibroblasts, CUGBP1 displaces CRT from the p21 mRNA and releases CRT-dependent repression of p21 translation leading to growth arrest and development of a senescent phenotype. These data present evidence that competition between RNA-binding proteins for the regulation of p21 translation determines cell fate.
Iakova
Polina
P
Department of Pathology and Huffington Center on Aging, Houston, TX, USA.
Wang
Guo-Li
GL
Timchenko
Lubov
L
Michalak
Marek
M
Pereira-Smith
Olivia M
OM
Smith
James R
JR
Timchenko
Nikolai A
NA
D020121:5' Untranslated Regions / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D000067879:CELF1 Protein; D037282:Calreticulin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D002455:Cell Division; D002460:Cell Line; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats
D020121:5' Untranslated Regions; C493956:CDKN1A protein, human; D000067879:CELF1 Protein; C102843:CELF1 protein, human; D037282:Calreticulin; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins