title: Multiple and cooperative phosphorylation events regulate the CREM activator function.
abstract: Phosphorylation is one of the major mechanisms by which the activity of transcription factors can be regulated. We have investigated the role of phosphorylation in the regulation of the transcription factor CREM. We show that the CREM tau activator is phosphorylated on multiple serine and threonine residues in vivo. Stimulation of various signal transduction pathways by forskolin, TPA or Ca2+ ionophore leads to enhanced phosphorylation of serine 117, concomitant with an increase in the transactivation potential of CREM tau. We have identified multiple kinases that can also phosphorylate S117 in vitro. Moreover, we show that casein kinase I and II cooperatively phosphorylate CREM tau on multiple residues, eliciting enhanced DNA binding. Cooperative phosphorylation is also observed with other kinases. These results show that the activity of CREM tau is regulated by multiple phosphorylation events, suggesting that CREM could be considered as a nuclear effector where signalling pathways may converge and/or cross-talk.
authors.affiliation: Laboratoire Génétique Moléculaire des Eucaryotes, CNRS, U184 de l'INSERM, Faculté de Médecine, Institut de Chimie Biologique, Strasbourg, France.
authors.forename: R P
authors.initials: RP
authors.lastname: de Groot
authors.forename: J
authors.initials: J
authors.lastname: den Hertog
authors.forename: J R
authors.initials: JR
authors.lastname: Vandenheede
authors.forename: J
authors.initials: J
authors.lastname: Goris
authors.forename: P
authors.initials: P
authors.lastname: Sassone-Corsi
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D051786:Cyclic AMP Response Element Modulator; D004247:DNA; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D004247:DNA; D011494:Protein Kinases