Regulation of fosB and DeltafosB mRNA expression: in vivo and in vitro studies.
The transcription factor DeltaFosB, a truncated splice isoform of FosB, accumulates in brain after several types of chronic stimulation. This accumulation is thought to be mediated by the unique stability of DeltaFosB compared to all other Fos family proteins. The goal of the present study was to determine if the relative expression of the two fosB isoforms is also regulated at the mRNA level, thereby further contributing to the selective accumulation of DeltaFosB after chronic stimulation. First, unlike the protein, the half-life of DeltafosB mRNA is only slightly longer than that of full-length fosB mRNA both in cultured cells in vitro and in the brain in vivo. Additionally, similar to c-fos, both fosB isoforms are induced abundantly in striatum after acute administration of amphetamine or stress, and partially desensitize after chronic exposures. Surprisingly, the relative ratio of DeltafosB to fosB mRNA increases most significantly after acute, not chronic, stimulation. Finally, overexpression of polypyrimidine tract binding protein (PTB1), which regulates RNA splicing, in cultured cells decreases the relative expression of DeltafosB compared to fosB mRNA. Together, these findings suggest that splicing of fosB pre-mRNA is regulated by the quantity of unspliced transcript available to the splicing machinery. These data provide fundamental information concerning the generation of DeltafosB mRNA, and indicate that the selective accumulation of DeltaFosB protein with chronic stimulation does not involve its preferential generation by RNA splicing.
Alibhai
Imran N
IN
Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Green
Thomas A
TA
Potashkin
Judith A
JA
Nestler
Eric J
EJ
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D038941:Polypyrimidine Tract-Binding Protein; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
D018765:Dopamine Uptake Inhibitors; C483820:Fosb protein, rat; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009124:Muscle Proteins; D016760:Proto-Oncogene Proteins c-fos; C475523:Ptbp1 protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein; D049452:Green Fluorescent Proteins; D000661:Amphetamine