Sandbox 7465: Difference between revisions
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'''INTRODUCTION''' | '''INTRODUCTION''' | ||
The transcription factor, DeltaFosB, is known to be involved in some of the physiological mechanisms linked to addiction and compulsive behaviors. Levels of DeltaFosB have been shown to increase in multiple regions of the brain in response to repeated drug exposure as well as stress, certain antipsychotic or antidepressant medications, electroconvulsive seizures, and certain lesions. DeltaFosB is a truncated, highly stable splice variant of the FosB transcription factor whose expression is regulated by alternative splicing of the FosB gene. Due to this splicing, DeltaFosB is known to have a half life five times that of FosB, which is thought to be a basis for addiction (James and Ruffle, 2014). | The transcription factor, DeltaFosB, is known to be involved in some of the physiological mechanisms linked to addiction and compulsive behaviors. Levels of DeltaFosB have been shown to increase in multiple regions of the brain in response to repeated drug exposure as well as stress, certain antipsychotic or antidepressant medications, electroconvulsive seizures, and certain lesions. DeltaFosB is a truncated, highly stable splice variant of the FosB transcription factor whose expression is regulated by alternative splicing of the FosB gene. Due to this splicing, DeltaFosB is known to have a half-life five times that of FosB, which is thought to be a basis for addiction (James and Ruffle, 2014). | ||
'''STRUCTURE''' | '''STRUCTURE''' | ||
The transcriptional factor DeltaFosB is unique in that it is a more stable form of FosB. There are two proposed regions that are cause for FosB’s instability; The amino acid sequences 278-337 and 278-337 contribute to proteasome-dependent FosB degradation. Proteins | The transcriptional factor DeltaFosB is unique in that it is a more stable form of FosB. There are two proposed regions that are cause for FosB’s instability; The amino acid sequences 278-337 and 278-337 contribute to proteasome-dependent FosB degradation. Proteins that undergo degradation are typically targeted by polyubiquitylation. HA-ubiquitin has been detected in FosB immunoprecipitations, but not in DeltaFosB, which is consistent with findings that DeltaFosB is formed through proteasomal degradation of FosB (Carle et al., 2007). | ||
In general, Transcription Factors contain three domains, a Trans-Activating Domain, a DNA Binding Domain, and a Signal Sensing Domain. Three domains have been consistently noted on FosB. (See Figure 1) The first is a bZIP domain, located on amino acids 155-218. The second is a basic motif, located on amino acids 157-182, and the third is a leucine-zipper, located on amino acids 183-211. | In general, Transcription Factors contain three domains, a Trans-Activating Domain, a DNA Binding Domain, and a Signal Sensing Domain. Three domains have been consistently noted on FosB. (See Figure 1) The first is a bZIP domain, located on amino acids 155-218. The second is a basic motif, located on amino acids 157-182, and the third is a leucine-zipper, located on amino acids 183-211. Figure 1 shows a FosB protein from Staphylococcus aureus, exhibiting all three of these domains | ||
Alternative splicing removes two destabilizing elements from FosB, generating the more stable, longer-lived DeltaFosB possessing a half-life increased by 5 fold. A 140-nucleotide sequence is removed from exon 4 of the primary FosB transcript, resulting in a one-nucleotide frameshift and the formation of an early stop codon (TGA). This results in premature termination of DeltaFosB translation; therefore, proteins translated from DeltaFosB mRNA are missing several amino acids present at the C-terminal of full-length FosB proteins that normally destabilize the proteins. FosB contains a sequence of amino acids (278-337) that is normally targeted for degradation by proteasomes. The DeltaFosB variant lacks this sequence resulting in increased stability as it is not recognized and therefore not degraded by proteasomes. Another contributing factor to the stability of DeltaFosB is phosphorylation by protein kinases | Alternative splicing removes two destabilizing elements from FosB, generating the more stable, longer-lived DeltaFosB possessing a half-life increased by 5 fold. A 140-nucleotide sequence is removed from exon 4 of the primary FosB transcript, resulting in a one-nucleotide frameshift and the formation of an early stop codon (TGA). This results in premature termination of DeltaFosB translation; therefore, proteins translated from DeltaFosB mRNA are missing several amino acids present at the C-terminal of full-length FosB proteins that normally destabilize the proteins. FosB contains a sequence of amino acids (278-337) that is normally targeted for degradation by proteasomes. The DeltaFosB variant lacks this sequence resulting in increased stability as it is not recognized and therefore not degraded by proteasomes. Another contributing factor to the stability of DeltaFosB is phosphorylation by protein kinases | ||
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This effect is underscored by a study which measured levels of DeltaFosB following a period of increased sexual activity (Pitchers et al., 2013). After a period of abstinence of 1, 7, or 28 days, levels of DeltaFosB in the Nucleus Accumbens were measured. As found in drug studies, DeltaFosB persisted in the NAc neurons of sexually active rats for at least 28 days after abstaining from the reward behavior. It can be concluded that there are similarities in the effects of both natural and drug rewards on the mesolimbic system. | This effect is underscored by a study which measured levels of DeltaFosB following a period of increased sexual activity (Pitchers et al., 2013). After a period of abstinence of 1, 7, or 28 days, levels of DeltaFosB in the Nucleus Accumbens were measured. As found in drug studies, DeltaFosB persisted in the NAc neurons of sexually active rats for at least 28 days after abstaining from the reward behavior. It can be concluded that there are similarities in the effects of both natural and drug rewards on the mesolimbic system. | ||
<StructureSection load='1stp' size='340' side='right' caption='This is a crystal structure of FosB from ''Staphylococcus aureus'''This is a similar structure to DeltaFosB, although it retains 2 destabilizing elements which are spliced in the DeltaFosB variant.The DeltaFosB transcription factor should include 3 domains, a transactivating domain, a DNA binding domain, and a signal sensing domain. DeltaFosB includes is a basic motif, a Leucine zipper, and a bZIP domain scene=''> | |||
