Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif.
Various stresses and DNA-damaging agents trigger transcriptional activity of p53 by post-translational modifications, making it a global regulatory switch that controls cell proliferation and apoptosis. Earlier we have shown that the novel MAR-associated protein SMAR1 interacts with p53. Here we delineate the minimal domain of SMAR1 (the arginine-serine-rich domain) that is phosphorylated by protein kinase C family proteins and is responsible for p53 interaction, activation, and stabilization within the nucleus. SMAR1-mediated stabilization of p53 is brought about by inhibiting Mdm2-mediated degradation of p53. We also demonstrate that this arginine-serine (RS)-rich domain triggers the various cell cycle modulating proteins that decide cell fate. Furthermore, phenotypic knock-down experiments using small interfering RNA showed that SMAR1 is required for activation and nuclear retention of p53. The level of phosphorylated p53 was significantly increased in the thymus of SMAR1 transgenic mice, showing in vivo significance of SMAR1 expression. This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the "guardian of the genome."
Jalota
Archana
A
National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, India.
Singh
Kamini
K
Pavithra
Lakshminarasimhan
L
Kaul-Ghanekar
Ruchika
R
Jameel
Shahid
S
Chattopadhyay
Samit
S
D020816:Amino Acid Motifs; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C485952:Banp protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine; D001120:Arginine; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2