p100 increases AT1R expression through interaction with AT1R 3'-UTR.
p100 protein (SND1, Tudor-SN) is a multifunctional protein that functions as a co-activator for several transcription factors, has a role in mRNA processing and participates in RNAi-induced silencing complex (RISC) with yet unknown function. In this study we identified a novel function for p100 as a regulator of angiotensin II type 1 receptor (AT1R) expression. The binding of p100 to AT1R 3'-untranslated region (3'-UTR) via staphylococcal nuclease-like (SN-like) domains increased receptor expression by decreasing the rate of mRNA decay and enhancing its translation. Overexpression of p100 increased AT1R expression, whereas decrease in p100 binding to 3'-UTR either by p100 silencing or by the deletion of p100 binding site downregulated receptor expression. The effect of p100 through AT1R 3'-UTR was independent of Argonaute2 (Ago2), a known p100 partner, and was thus RISC-independent. Nucleotides 118 to 120 of the AT1R 3'-UTR were found to be critical for the binding of p100 to 3'-UTR. In summary, p100 is a multifunctional regulator of gene expression that regulates transcription, mRNA maturation, and as described in this article, also mRNA stability and translation.
Paukku
Kirsi
K
Research Program for Molecular Medicine, Biomedicum Helsinki, University of Helsinki, Finland. kpaukku@mappi.helsinki.fi
Kalkkinen
Nisse
N
Silvennoinen
Olli
O
Kontula
Kimmo K
KK
Lehtonen
Jukka Y A
JY
D020413:3' Untranslated Regions / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D060565:Argonaute Proteins; D001665:Binding Sites; D002460:Cell Line; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004720:Endonucleases; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D034743:RNA-Induced Silencing Complex / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics*
D020413:3' Untranslated Regions; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; D035683:MicroRNAs; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034743:RNA-Induced Silencing Complex; D044140:Receptor, Angiotensin, Type 1; D008156:Luciferases; D004720:Endonucleases; C095221:SND1 protein, human