Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins.
The CREB family of proteins are critical mediators of gene expression in response to extracellular signals and are essential regulators of adaptive behavior and long-term memory formation. The TORC proteins were recently described as potent CREB coactivators, but their role in regulation of CREB activity remained unknown. TORC proteins were found to be exported from the nucleus in a CRM1-dependent fashion. A high-throughput microscopy-based screen was developed to identify genes and pathways capable of inducing nuclear TORC accumulation. Expression of the catalytic subunit of PKA and the calcium channel TRPV6 relocalized TORC1 to the nucleus. Nuclear accumulation of the three human TORC proteins was induced by increasing intracellular cAMP or calcium levels. TORC1 and TORC2 translocation in response to calcium, but not cAMP, was mediated by calcineurin, and TORC1 was shown to be directly dephosphorylated by calcineurin. TORC function was shown to be essential for CRE-mediated gene expression induced by cAMP, calcium, or GPCR activation, and nuclear transport of TORC1 was sufficient to activate CRE-dependent transcription. Drosophila TORC was also shown to translocate in response to calcineurin activation in vivo. Thus, TORC nuclear translocation is an essential, conserved step in activation of cAMP-responsive genes.
Bittinger
Mark A
MA
Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
McWhinnie
Elizabeth
E
Meltzer
Jodi
J
Iourgenko
Vadim
V
Latario
Brian
B
Liu
Xiulin
X
Chen
Chein Hwa
CH
Song
Chuanzheng
C
Garza
Dan
D
Labow
Mark
M
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004330:Drosophila; D005786:Gene Expression Regulation / Q000502:physiology*; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D028884:Karyopherins / Q000378:metabolism; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D050916:TRPV Cation Channels; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D000097606:Exportin 1 Protein
D019703:Calcineurin; D015220:Calcium Channels; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D017931:DNA Primers; D018076:DNA, Complementary; D049452:Green Fluorescent Proteins; D028884:Karyopherins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D050916:TRPV Cation Channels; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C115163:CREB1 protein, human; C493245:CRTC2 protein, human; C120776:TRPV6 channel