Sandbox 7465: Difference between revisions
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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 which 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). | 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 which 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 | 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. | ||
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 | ||
'''FUNCTION''' | '''FUNCTION''' | ||
FosB is encoded by the FOSB gene located on human chromosome 19. The Fos gene family consists of four main members (Fos, FosB, FosL1, and FosL2) that heterodimerize with Jun family proteins. The Leucine Zipper motif found in FosB is conserved in DeltaFosB, therefore the heterodimerization with Jun family proteins will form the Activator Protein-1 (AP-1) transcription factor complex. AP-1 complexes function to regulate gene expression by binding to AP-1 sites on promoter sequences. DeltaFosB makes more than 50 AP-1 dimeric complexes that bind to promoter regions of a wide variety of mammalian genes. For example, DeltaFosB has been shown to upregulate gene expression of NFκB, CDK5, and GluR2 involved with addiction. | FosB is encoded by the FOSB gene located on human chromosome 19. The Fos gene family consists of four main members (Fos, FosB, FosL1, and FosL2) that heterodimerize with Jun family proteins. The Leucine Zipper motif found in FosB is conserved in DeltaFosB, therefore the heterodimerization with Jun family proteins will form the Activator Protein-1 (AP-1) transcription factor complex. AP-1 complexes function to regulate gene expression by binding to AP-1 sites on promoter sequences. DeltaFosB makes more than 50 AP-1 dimeric complexes that bind to promoter regions of a wide variety of mammalian genes. For example, DeltaFosB has been shown to upregulate gene expression of NFκB, CDK5, and GluR2 involved with addiction (Jorrissen et al., 2007). | ||
DeltaFosB isoforms accumulate in the dopaminergic pathways of the brain with chronic drug use because of their long half-lives. The transcription factor will remain expressed in neurons for weeks following the discontinuation of drug use. This is made possible by the increased stability resulting from the lack of degron domains present in the C-terminus of FosB and the phosphorylation of DeltaFosB at its N terminus. These alterations resulting in the accumulation of DeltaFosB could potentially explain the long-term effects of drug withdrawal resulting from changes in gene expression (Nester, 2008). | DeltaFosB isoforms accumulate in the dopaminergic pathways of the brain with chronic drug use because of their long half-lives. The transcription factor will remain expressed in neurons for weeks following the discontinuation of drug use. This is made possible by the increased stability resulting from the lack of degron domains present in the C-terminus of FosB and the phosphorylation of DeltaFosB at its N terminus. These alterations resulting in the accumulation of DeltaFosB could potentially explain the long-term effects of drug withdrawal resulting from changes in gene expression (Nester, 2008). | ||
It is likely that DeltaFosB plays a role in mediating some of the neural and behavioral sensitivity resulting from chronic drug exposure. Kelz and colleagues (1999) found that mice induced to express high levels of DeltaFosB in the area of the nucleus accumbens that is associated with production of the transcription factor had heightened responses to cocaine exposure. DeltaFosB-expressing mice were seen to have higher levels of activity compared to their negative counterparts upon initial cocaine injection as well as sustained increase in activity upon subsequent cocaine injections. Expression of DeltaFosB has also been shown to increase responses to the rewarding effects of cocaine (Kelz et al., 1999). DeltaFosB-positive mice spent approximately 3 times longer in a compartment associated with drug exposure than did mice not expressing DeltaFosB. | It is likely that DeltaFosB plays a role in mediating some of the neural and behavioral sensitivity resulting from chronic drug exposure. Kelz and colleagues (1999) found that mice induced to express high levels of DeltaFosB in the area of the nucleus accumbens that is associated with production of the transcription factor had heightened responses to cocaine exposure. DeltaFosB-expressing mice were seen to have higher levels of activity compared to their negative counterparts upon initial cocaine injection as well as sustained increase in activity upon subsequent cocaine injections. Expression of DeltaFosB has also been shown to increase responses to the rewarding effects of cocaine (Kelz et al., 1999). DeltaFosB-positive mice spent approximately 3 times longer in a compartment associated with drug exposure than did mice not expressing DeltaFosB. | ||
