Lithium enhances CRTC oligomer formation and the interaction between the CREB coactivators CRTC and CBP--implications for CREB-dependent gene transcription.
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Lithium enhances CRTC oligomer formation and the interaction between the CREB coactivators CRTC and CBP--implications for CREB-dependent gene transcription. / Heinrich, Annette; Heyde, von der; Sophie, Anne; Böer, Ulrike; Phu, Do Thanh; Oetjen, Elke.
In: CELL SIGNAL, Vol. 25, No. 1, 1, 2013, p. 113-125.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Lithium enhances CRTC oligomer formation and the interaction between the CREB coactivators CRTC and CBP--implications for CREB-dependent gene transcription.
AU - Heinrich, Annette
AU - Heyde, von der
AU - Sophie, Anne
AU - Böer, Ulrike
AU - Phu, Do Thanh
AU - Oetjen, Elke
PY - 2013
Y1 - 2013
N2 - Lithium salts are important drugs to treat bipolar disorder. Previous work showed that lithium by enforcing the interaction between the transcription factor CREB and its coactivator CRTC1 enhanced cAMP-stimulated CREB-dependent gene transcription. Both CREB and CRTC have been implicated in neuronal adaptation, which might underlie lithium's therapeutic action. In the present study the mechanisms of lithium action on cAMP-induced CREB-dependent gene transcription were further elucidated. Transient transfection assays revealed that all three CRTC isoforms conferred lithium responsiveness to CREB whereas their intrinsic transcriptional activities remained unchanged by lithium, suggesting a conformational change of CREB or CRTC by lithium. In in vitro protein-protein interaction assays lithium enhanced the interaction between CREB and both coactivators CRTC and CBP. Furthermore, lithium enforced the oligomerization of CRTC, a prerequisite for CREB interaction. For further evaluation it was investigated whether lithium competes with magnesium, which coordinates the conformation of the CREB basic region leucine zipper (bZip). Mutational analysis of the magnesium coordinating lysine-290 within the bZip, in vitro and intracellular interaction assays and luciferase reporter-gene assays revealed that the effect of lithium on the CREB-CRTC interaction or on the transcriptional activity, respectively, was not affected by the mutation, thus excluding a magnesium-lithium competition. However, the CREB-CRTC interaction was strongly increased in lysine-290-mutants thereby extending the CRTC-CREB interaction domain. Taken together the results exclude a competition between lithium and magnesium at the bZip, but suggest that lithium by enforcing the CRTC-oligomer formation and the interaction of CREB-CBP-CRTC enhances cAMP-induced CREB-dependent gene transcription.
AB - Lithium salts are important drugs to treat bipolar disorder. Previous work showed that lithium by enforcing the interaction between the transcription factor CREB and its coactivator CRTC1 enhanced cAMP-stimulated CREB-dependent gene transcription. Both CREB and CRTC have been implicated in neuronal adaptation, which might underlie lithium's therapeutic action. In the present study the mechanisms of lithium action on cAMP-induced CREB-dependent gene transcription were further elucidated. Transient transfection assays revealed that all three CRTC isoforms conferred lithium responsiveness to CREB whereas their intrinsic transcriptional activities remained unchanged by lithium, suggesting a conformational change of CREB or CRTC by lithium. In in vitro protein-protein interaction assays lithium enhanced the interaction between CREB and both coactivators CRTC and CBP. Furthermore, lithium enforced the oligomerization of CRTC, a prerequisite for CREB interaction. For further evaluation it was investigated whether lithium competes with magnesium, which coordinates the conformation of the CREB basic region leucine zipper (bZip). Mutational analysis of the magnesium coordinating lysine-290 within the bZip, in vitro and intracellular interaction assays and luciferase reporter-gene assays revealed that the effect of lithium on the CREB-CRTC interaction or on the transcriptional activity, respectively, was not affected by the mutation, thus excluding a magnesium-lithium competition. However, the CREB-CRTC interaction was strongly increased in lysine-290-mutants thereby extending the CRTC-CREB interaction domain. Taken together the results exclude a competition between lithium and magnesium at the bZip, but suggest that lithium by enforcing the CRTC-oligomer formation and the interaction of CREB-CBP-CRTC enhances cAMP-induced CREB-dependent gene transcription.
KW - Animals
KW - Humans
KW - Cricetinae
KW - Mutation
KW - Cell Line, Tumor
KW - Transfection
KW - Genes, Reporter
KW - Protein Isoforms/genetics/metabolism
KW - Protein Interaction Mapping
KW - Transcription, Genetic/drug effects
KW - CREB-Binding Protein/metabolism
KW - Cyclic AMP Response Element-Binding Protein/genetics/metabolism
KW - Lithium Chloride/pharmacology
KW - Magnesium Chloride/pharmacology
KW - Protein Multimerization/drug effects
KW - Transcription Factors/genetics/metabolism
KW - Animals
KW - Humans
KW - Cricetinae
KW - Mutation
KW - Cell Line, Tumor
KW - Transfection
KW - Genes, Reporter
KW - Protein Isoforms/genetics/metabolism
KW - Protein Interaction Mapping
KW - Transcription, Genetic/drug effects
KW - CREB-Binding Protein/metabolism
KW - Cyclic AMP Response Element-Binding Protein/genetics/metabolism
KW - Lithium Chloride/pharmacology
KW - Magnesium Chloride/pharmacology
KW - Protein Multimerization/drug effects
KW - Transcription Factors/genetics/metabolism
M3 - SCORING: Journal article
VL - 25
SP - 113
EP - 125
JO - CELL SIGNAL
JF - CELL SIGNAL
SN - 0898-6568
IS - 1
M1 - 1
ER -
