Modulation of Heat Shock Transcription Factor 1 as a Therapeutic Target for Small Molecule Intervention in Neurodegenerative Disease

ABSTRACT Heat shock transcription factor 1 (HSF-1) activates the transcription of heat shock genes in eukaryotes. Under normal physiological growth conditions, HSF-1 is a monomer. Its transcriptional activity is repressed by constitutive phosphorylation. Upon activation, HSF-1 forms trimers, acquires DNA binding activity, increases transcriptional activity, and appears as punctate granules in the nucleus. In this study, using bromouridine incorporation and confocal laser microscopy, we demonstrated that newly synthesized pre-mRNAs colocalize to the HSF-1 punctate granules after heat shock, suggesting that these granules are sites of transcription. We further present evidence that glycogen synthase kinase 3β (GSK-3β) and extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) participate in the down regulation of HSF-1 transcriptional activity. Transient increases in the expression of GSK-3β facilitate the disappearance of HSF-1 punctate granules and reduce hsp-70 transcription after heat shock. We have also shown that ERK is the priming kinase for GSK-3β. Taken together, these results indicate that GSK-3β and ERK MAPK facilitate the inactivation of activated HSF-1 after heat shock by dispersing HSF-1 from the sites of transcription.

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Homology Modeling and Characterization of Novel Stress Inducing Genes and their Split Sites Recognition in the Genome of Zebra Fish (Danio Rario) by Employing Special Consensus Pattern Matching Algorithms- using an in-Silico Method.

International Journal of Engineering and Advanced Technology - Regular Issue ◽

10.35940/ijeat.a2003.109119 ◽

2019 ◽

Vol 9 (1) ◽

pp. 6715-6720

Keyword(s):

Transcription Factor ◽

Heat Shock ◽

Pattern Matching ◽

Binding Sites ◽

In Silico ◽

3D Structure ◽

Transcription Factor Binding Sites ◽

Heat Shock Transcription Factor ◽

Zebra Fish ◽

Transcription Factor 1

Zebra fish has long been considered to be as a strong animal model in biology and modern genetics; however now a days its gaining lot of importance in environmental studies as well. The readily availability of entire genome sequences made to permit carrying out in silico studies at Genomic level. As everyone is known that stress is much more complex and complicated process that involves so much of gene regulations known as up regulation and down regulation, the corresponding stress proteins, broadly known as heat shock proteins. In the current study, the potential transcription factor binding sites were traced out by using bioinformatics tools and about 50 heat shock protein genes were predicted by using special alogorithms using pattern matching and position weight matrices. The 3D structure of DNA-binding domain of HSTF-1 ( Heat Shock Transcription factor-1) which is crucial for regulating heat shot proteins was traced out and builted by using homology modelling methods. The 3D structure of the heat shock transcription factor-1 and together with predicted transcription factor binding sites may be validated in future experimental works which would help us in understanding the complex responsive stress mechanisms lying in Zebra fish.

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