Presenilin-2 regulates the degradation of RBP-Jk protein through p38 mitogen-activated protein kinase.
Transcriptional regulation performs a central role in Notch1 signaling by recombining binding protein Suppressor of Hairless (RBP-Jk)--a signaling pathway that is widely involved in determination of cell fate. Our earlier work demonstrated the possible regulation of the Notch1-RBP-Jk pathway through protein degradation of RBP-Jk; however, the potential regulator for the degradation of RBP-Jk remains to be determined. Here, we report that the expression of endogenous and exogenous RBP-Jk was increased significantly in cells treated with proteasome- and lysosome-specific inhibitors. The effects of these inhibitors on RBP-Jk occurred in a dose- and time-dependent manner. The level of RBP-Jk protein was higher in presenilin-2 (PS2)-knockout cells than in presenilin-1 (PS1)-knockout cells. Furthermore, the level of RBP-Jk was decreased by expression of PS2 in PS1 and PS2 double-knockout cells. We also found that PS1-knockout cells treated with a specific inhibitor of p38 mitogen-activated protein kinase ∂ (MAPK) had significantly increased levels of RBP-Jk. p38 MAPK phosphorylates RBP-Jk at Thr339 by physical binding, which subsequently induces the degradation and ubiquitylation of the RBP-Jk protein. Collectively, our results indicate that PS2 modulates the degradation of RBP-Jk through phosphorylation by p38 MAPK.
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 500-757,  Republic of Korea.
Su-Man
SM
Kim
Mi-Yeon
MY
Kim
Eun-Jung
EJ
Ann
Jung-Soon
JS
Mo
Ji-Hye
JH
Yoon
Hee-Sae
HS
Park
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000096:biosynthesis / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors; D059748:Proteolysis; D051881:Receptor, Notch1 / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007976:Leupeptins; C497761:NOTCH1 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D061988:Proteasome Inhibitors; C497570:RBPJ protein, human; D051881:Receptor, Notch1; D000643:Ammonium Chloride; C063261:acetylleucyl-leucyl-norleucinal; C067713:lactacystin; D002738:Chloroquine; D048051:p38 Mitogen-Activated Protein Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine