Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20226 (TATA-binding protein)
 1,297 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxia type 17 (SCA17) is caused by CAG repeat expansion in the TATA-box binding protein gene. Studies of several polyglutamine (polyQ) expansion diseases have suggested that the expanded polyQ proteins misfold and induce oxidative stress to contribute to cell death. Substantial deficits in peripheral tissues including lymphocytes have been shown and these peripheral abnormalities could also be found in neurons possessing polyQ disease proteins. In this study, we used a lymphoblastoid cell model to investigate the functional implication of SCA17 expanded alleles and assess the potential therapeutic strategies that may ameliorate the effects of expanded polyQ. Proteomics studies of patient/control pairs including two-dimensional (2-D) gel electrophoresis, mass spectrometry and immunoblotting were conducted. A total of 8 proteins with reduced expression changes greater than 1.3-fold were identified, including previously reported HSPA5 and HSPA8. Among 6 proteins further semi-quantified by immunoblotting and real-time PCR, the reduced expression of HYOU1, PDIA3, P4HB, NQO1 and HMOX1 was confirmed. Treatment with resveratrol and genipin up-regulated NQO1 and HMOX1 expression and reduced oxidative stress in patients' lymphoblastoid cells. The results illustrate downregulation of proteins involved in the endoplasmic reticulum stress response (HYOU1, HSPA5, PDIA3, and P4HB) and Nrf2-ARE signaling (NQO1 and HMOX1) in SCA17 lymphoblastoid cells. Compounds increasing anti-oxidative activity such as resveratrol and genipin may serve as a potential therapeutic strategy for SCA17.
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PMID:Downregulation of proteins involved in the endoplasmic reticulum stress response and Nrf2-ARE signaling in lymphoblastoid cells of spinocerebellar ataxia type 17. 2441 82

The parasite Trypanosoma brucei is the causative agent of human African sleeping sickness. T. brucei genes are constitutively transcribed in polycistronic units that are processed by trans-splicing and polyadenylation. All mRNAs are trans-spliced to generate mRNAs with a common 5' exon derived from the spliced leader RNA (SL RNA). Persistent endoplasmic reticulum (ER) stress induces the spliced leader silencing (SLS) pathway, which inhibits trans-splicing by silencing SL RNA transcription, and correlates with increased programmed cell death. We found that during ER stress induced by SEC63 silencing or low pH, the serine-threonine kinase PK3 translocated from the ER to the nucleus, where it phosphorylated the TATA-binding protein TRF4, leading to the dissociation of the transcription preinitiation complex from the promoter of the SL RNA encoding gene. PK3 loss of function attenuated programmed cell death induced by ER stress, suggesting that SLS may contribute to the activation of programmed cell death.
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PMID:Phosphorylation of the TATA-binding protein activates the spliced leader silencing pathway in Trypanosoma brucei. 2518 57

The unfolded protein response (UPR) is induced when the quality control machinery of the cell is overloaded with unfolded proteins or when one of the functions of the endoplasmic reticulum (ER) is perturbed. Here, I describe UPR in yeast and mammals, and compare it to what we know about pathogenic fungi and the parasitic protozoans from the order kinetoplastida, focusing on the novel pathway the spliced leader silencing (SLS) in Trypanosoma brucei. Trypanosomes lack conventional transcription regulation, and thus, lack most of the UPR machinery present in other eukaryotes. Trypanosome genes are transcribed in polycistronic units that are processed by trans-splicing and polyadenylation. In trans-splicing, which is essential for processing of each mRNA, an exon known as the spliced leader (SL) is added to all mRNAs from a small RNA, the SL RNA. Under severe ER stress, T. brucei elicits the SLS pathway. In SLS, the transcription of the SL RNA gene is extinguished, and the entire transcription complex dissociates from the SL RNA promoter. Induction of SLS is mediated by an ER-associated kinase (PK3) that migrates to the nucleus, where it phosphorylates the TATA-binding protein (TRF4), leading shut-off of SL RNA transcription. As a result, trans-splicing is inhibited and the parasites activate a programmed cell death (PCD) pathway. Despite the ability to sense the ER stress, the different eukaryotes, especially unicellular parasites and pathogenic fungi, developed a variety of unique and different ways to sense and adjust to this stress in a manner different from their host.
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PMID:The response of trypanosomes and other eukaryotes to ER stress and the spliced leader RNA silencing (SLS) pathway in Trypanosoma brucei. 2598 70